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Non-receptor protein tyrosine kinases

Article  in  Frontiers in Bioscience · June 2003

DOI: 10.2741/1106 · Source: PubMed

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Alexander Y Tsygankov
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[Frontiers in Bioscience 8, s595-635, May 1, 2003]

NON-RECEPTOR PROTEIN TYROSINE KINASES

Alexander Y. Tsygankov

Department of Microbiology & Immunology, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA
19140

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Families of non-receptor protein tyrosine kinases
3.1. Src
3.2. Csk
3.3. Syk
3.4. Tec
3.5. Jak
3.6. Fak
3.7. Abl
3.8. Fes
3.9. Frk
3.10. Ack
4. Concluding remarks
5. Acknowledgements
6. References

1. ABSTRACT

The protein tyrosine kinases (PTKs) are enzymes of the human genome are PTKs (1-4). The PTK
catalyzing the transfer of the gamma-phosphate group of superfamily is enormously diverse. First of all, PTKs are
ATP to the hydroxyl groups of specific tyrosine residues in clearly divided into two groups according to the presence
peptides. Although phosphotransfer reactions catalyzed by of transmembrane and extracellular domains, which enable
various PTKs are similar with regard to their basic PTKs possessing them to recognize extracellular ligands, in
mechanisms, their biological functions demonstrate a particular, various peptide growth factors. Specific ligands
considerable degree of specificity. PTKs are divided into and intracellular signaling pathways induced by them have
two groups according to the presence of transmembrane been identified for many, albeit not for all, membrane-
and extracellular domains. Whereas most PTKs possess spanning PTKs (5). Whereas most PTKs are of receptor
these domains, which render them capable of recognizing nature, many PTKs lack the transmembrane and
extracellular ligands, many PTKs lack these sequences and extracellular sequences and are therefore referred to as non-
are therefore referred to as non-receptor or non- receptor or non-transmembrane PTKs. Thirty-two genes
transmembrane PTKs. Thirty-two genes encoding for non- encoding for non-receptor PTKs are present in the human
receptor PTKs are present in the human genome. The genome. The current review, focussing on mammalian non-
current review focuses on the composition, structure, receptor PTKs, is not intended to replace a number of
expression, functions and regulation of the mammalian excellent reviews on this subject (see above), but to give a
non-receptor PTK families. brief overview of these proteins for the current special issue
on protein tyrosine phosphorylation. The information on
2. INTRODUCTION receptor PTKs can be obtained in a number of recent
reviews (5-18).
The protein tyrosine kinases (PTKs) are enzymes
catalyzing the transfer of the gamma-phosphate group of PTKs have been found only in the multicellular
ATP to the hydroxyl groups of specific tyrosine residues in animal organisms. This peculiarity appears to make
peptides. Although phosphotransfer reactions catalyzed by biological sense, since PTKs are primarily involved in the
various PTKs are similar with regard to the basic regulation of the cellular functions that are directly related
mechanisms, the recognition of substrates by PTKs and, to the multicellular status of the organism, such as growth,
therefore, subsets of proteins phosphorylated by them show differentiation, and cell-cell and cell-extracellular matrix
a considerable degree of specificity. interactions. However, the significance of the apparent lack
of PTKs in the multicellular plant organisms is not clear
In agreement with the general prevalence of (19).
serine/threonine phosphorylation over tyrosine
phosphorylation in the cells, the genes encoding for PTKs Each PTK possesses a functional kinase domain
are notably fewer than those encoding for serine/threonine capable of catalyzing the transfer of phosphate from ATP
protein kinases, only about 1/6 of all protein kinase genes to tyrosine residues essentially independent of the presence

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Non-receptor protein tyrosine kinases

Figure 1. Domain structure of non-receptor protein tyrosine kinase families. The overall length of kinases and the positions of
their domains (rulers at the top and at the bottom of the figure are graduated in amino acid residues) have been averaged for each
family, unless substantial differences exist between family members. Thus, Tec-family structure is based on the typical members
(Tec, Btk, Itk, and Bmx), while Txk lacking both PH and TH domains has been omitted from averaging. The DNA binding
domain in the Abl-family structure is shown, although it is not conserved in Arg. The presented structure of Ack family is that of
Ack1, because including Tnk1 in the averaging would not be meaningful, since Tnk1 is substantially shorter than Ack1 and lacks
the CRIB domain. The details of the domain structure and interactions are given in the text.

of other structural elements of PTKs. The kinase domains binding to phosphotyrosyl residues (25, 26), whereas SH3
are highly conserved among receptor and non-receptor binds to specific proline-rich motifs present in many
PTKs. Furthermore, PTK catalytic domains are similar to proteins (27, 28). These domains are not unique for PTKs,
those of serine/threonine and dual-specificity protein but are present instead in numerous eukaryotic proteins.
kinases, although several subdomain motifs appear to be
unique for PTKs (20). The PTKs may be grouped into distinct families
based on their overall domain structure, divergence of
Based on the solved crystal structures of several amino acid sequences of their kinase domains and the
PTKs, the catalytic domain of PTKs is similar to that of exon/intron organization of their genes. As a result of this
Ser/Thr protein kinases consisting of two lobes, N- analysis, the mammalian non-receptor PTKs are clustered
terminal, which interacts with the phosphate groups of into 10 families (figure 1). In the current review, a brief
ATP, and C-terminal, which provides substrate-binding overview of structure, expression, role in signal
sites for ATP and peptides. The C-terminal domain transduction, biological functions and regulation is given
includes the activation loop, a segment typically containing for each family.
Tyr, Ser or Thr residues that can be phosphorylated. In its
non-phosphorylated state, the activation loop tends to 3. FAMILIES OF NON-RECEPTOR PTKs
hinder substrate binding. Phosphorylation of these residues
increases kinase activity (reviewed in (21-24)). 3.1. Src
The Src family of PTKs with its eight members is
In addition to catalytic domains, the structure of the largest one among non-receptor PTKs. Mouse orthologs
PTKs includes other well-characterized protein domains. are known for all eight human Src-family members, as they
Typically, these domains mediate inter- and intramolecular are for almost all other human PTKs. A substantial number
interactions of PTKs, thus playing an important role in their of rat and chicken orthologs of human Src-family PTKs
functional regulation. Of these non-catalytic domains, SH2 have been identified. However, it is possible that non-
and SH3 domains are most frequently present in non- mammalian species, such as the chicken, may have Src-
receptor PTKs. The SH2 domain is capable of specific family PTKs that lack human or mammalian orthologs. For

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Non-receptor protein tyrosine kinases

example, it appears that no mammalian ortholog exists for emanate from the corresponding receptors (48, 49, 69-78).
the Yrk kinase of Src-family from chicken (1, 29). In many cases, the first and the most critical target of Src-
family PTKs are the tyrosine residues within the immune
All PTKs of Src-family have a common structure receptor tyrosine-based activation motifs (ITAMs) of the
consisting of the N-terminal sequence containing fatty acid- MIRRs (79-82). Each of these motifs includes two Tyr-X-
modification sites followed by a region in which the X-Leu/Ile sequences separated by 7-9 amino acid residues.
sequences of Src-family PTKs show the lowest degree of Both tyrosines should become phosphorylated on a single
intra-family homology or the so-called “unique domain.” ITAM to form a docking site for the Syk-family PTKs,
Next to the N-terminal region is located an SH3 domain which tightly bind to doubly phosphorylated ITAMs with
followed by an SH2 domain, which is followed, in turn, by their double SH2 domains position in tandem to each other
a tyrosine kinase domain. The C-terminal part of Src- (see below). In addition to phosphorylating ITAMs, Src-
family PTKs contains the tyrosine residue that plays an family PTKs appear to phosphorylate a number of other
important role in the regulation of their activity (see substrates, including other PTKs, thus playing an important
below). role in the regulation of the latter (see below).

Comparison of amino acid sequences of Src-family It should be noted that in spite of certain
PTKs allows us to separate them into two subfamilies. The similarities between members of Src-family PTKs
first subfamily includes Src, the prototypical member of the regarding the molecular basis of their involvement in
family, Fyn, Yes and Fgr. (Here and throughout the entire text, receptor signaling and in spite of some redundancy and
the prefix “c” is omitted for all cellular PTKs. If no prefix overlapping of their functions, the roles of these PTKs in
denoting a viral or another deregulated PTK form is used, it is signaling are highly specific. This conclusion is supported
presumed that a cellular form of PTK is mentioned.) The by numerous biochemical and genetic studies quoted
second one includes Lck, Blk, Lyn and Hck. Interestingly, this above, as well as by gene-targeting experiments with Src-
division corresponds to the tissue expression of these PTKs. family PTKs (see below).
Kinases of the first subfamily are widely expressed in various
tissues, whereas expression of the second subfamily is An interesting characteristic of the localization of
restricted to hematopoietic cells. Furthermore, expression of Src-family PTKs is that they are preferentially localized to
each PTK of the second family is specific for certain cell types. cholesterol- and glycolipid-enriched membrane
For instance, expression of Lck is restricted to T and NK cells, microdomains frequently referred to as lipid rafts (83-86).
whereas Blk is expressed in B cells only (reviewed in (30, 31)). Localization of Src-family PTKs, as well as other PTKs
and their substrates, to the lipid rafts is likely to be
Although Src-family PTKs lack a transmembrane important for the activation of immune cells (87-96).
domain, they are localized primarily to cellular membranes,
including plasma, perinuclear and endosomal membranes Signal transduction through MIRRs is not the
(32-34). The membrane localization of Src-family PTKs is only function of Src-family PTKs. They also participate in
due, to a substantial extent, to their N-terminal post- signaling through other receptors, including the cytokine
translation modifications with fatty acid moieties, receptors (97-105) and the receptor PTKs (106-111).
myristoylation (35-37) and palmitoylation (38-40). The Participation of Src-family PTKs in cytokine signaling may
former appears to be irreversible, whereas the latter is involve functional interactions with Jak-family PTKs (112-
reversible, making it possible to regulate the degree of 114).
hydrophobicity of Src-family PTKs.
Src-family PTKs are also involved in the
Localization of individual Src-family PTKs is regulation of cytoskeletal rearrangements in various cell
also dependent on their specific interactions with other types. This involvement is due to the ability of Src-family
cellular proteins. For example, Lck binds to the cytosolic PTKs to associate with various cytoskeletal proteins,
tails of the CD4 and CD8 co-receptors in T lymphocytes including focal adhesion kinase (Fak) (115-125). These
(41, 42) and is, therefore, localized in the proximity of the interactions appear to be critical for the regulation of
T-cell receptor complex (TCR/CD3) (43-45), where it plays assembly/disassembly of focal adhesion complexes and for
an important role in TCR/CD3-induced signaling (44, 46, the transmission of signals from the focal adhesions-linked
47). Fyn is another Src-family PTK participating in integrins to the system regulating actin cytoskeleton
TCR/CD3-induced signaling (48-51). However, unlike Lck, assembly.
Fyn is associated directly with the cytoplasmic tails of
TCR/CD3 (52, 53). Other Src-family PTKs expressed in In the above-discussed phenomena, activation of
the cells of the immune system have also been shown to PTKs appeared to be the first step of signaling pathways.
physically associate with multi-chain immune recognition Initiation of MIRR-mediated signaling by Src-family PTKs
receptors (MIRRs), including the B-cell antigen receptor may be considered the “classical” example of such a role.
complex (BCR) (54-57) and the receptors for the Fc However, Src-family PTKs may also function as
portions of IgG (58-64) and IgE (65-68). downstream elements of signal transduction pathways. For
instance, substantial evidence has been accumulated that
The function of Src-family PTKs associated with Src-family PTKs may act as effectors of trimeric G proteins
these and other surface receptors of immune cells appears (126, 127). Furthermore, the naturally occurring form of
to be the triggering of signal transduction pathways that Fgr lacking a myristoylation site (128) and, under certain

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Non-receptor protein tyrosine kinases

conditions, the full-length Src (129) have been found in the Furthermore, based on their consensus sequence, the
nucleus. Although the functions of nucleus-localized Src- autophosphorylation sites of Src-family PTKs represent
family PTKs are still unclear, Src has been implicated in potential substrates for other PTKs (159). Indeed,
regulation of cell cycle progression and mitosis (130-135). phosphorylation of tyrosine 394 of Lck that corresponds to
Tyr-419 of human Src has been observed in inactive Lck in
Targeted disruptions of Src-family PTK genes cells lacking endogenous wild-type Lck (160), as well as in
confirmed their biological importance and highlighted the cells lacking any Src-family PTKs (161).
specific functions of individual Src-family PTKs. The Phosphorylation of the tyrosine residue corresponding to
biological consequence of the loss of Src turned out to be Tyr-419 of human Src, regardless of the specific mode by
osteopetrosis due to a defective osteoclast function (136, which it is achieved, causes displacement of this tyrosine
137). Consistent with the involvement of Lck in T-cell from a hydrophobic pocket formed by both lobes of the
signaling, Lck-deficient mice demonstrated a profound PTK catalytic domain and results in the correct positioning
block in T-cell development along with the impaired of all key catalytic residues and in the formation of the
signaling and biological responses of the remaining few substrate binding surfaces, thus leading to the full
mature T cells (138-140). The effect of Lck disruption on activation of the Src-family enzymes (162-167).
T-cell development is apparently due to the essential role of
this kinase in transducing signals from the pre-TCR that are The second major tyrosine phosphorylation site
required for the progression of thymocytes from the of Src-family PTKs, which is located in their C-terminal
double-negative to the double-positive stage (141, 142). In domain, is phosphorylated by Csk-family PTKs (see
contrast, targeted disruption of Fyn, which is also involved below). Phosphorylation of this tyrosine causes its
in lymphocyte signaling, caused no effects in T-cell intramolecular interaction with an SH2 domain (168-171).
development and only mild defects in T-cell signaling (48, The binding between the SH2 domain and the C-terminal
49). However, Fyn-negative mice show numerous and quite phosphorylated tyrosine per se does not block or alter the
severe defects in the architecture and functions of the active site of the kinase domain. Instead, it induces the
central nervous system (143-146), as well as the defect in binding of the SH3 domain to the linker region connecting
keratinocyte development (147). A deficiency in Lyn the SH2 domain and the kinase domain accompanied by the
resulted in a substantial reduction in the number of binding of the linker region to the kinase domain. These
peripheral B cells and the level of their BCR-mediated intramolecular interactions prevent binding of ATP to the
responses, as well as in developing autoimmunity (148, critical catalytic residues rendering Src-family PTKs
149). The latter can be explained by possible defects in inactive. The residue corresponding to Tyr-419 of human
negative selection of autoreactive B-cell progenitors. Src is located in the hydrophobic pocket and is protected
from phosphorylation in the inactive form of Src-family
No overt phenotypic changes have been observed PTKs (163-167, 172).
in yes-, hck-, fgr- or blk-null mice (reviewed in (150)).
These findings suggest that a high degree of redundancy Consistent with these findings, disruption of the
exists between different members of the Src family. This interactions that negatively regulate Src-family PTKs
notion is supported by findings indicating that double increases their enzymatic activity and cell-transformation
knock-out mutations can dramatically exacerbate potential. Such disruption may be achieved by mutating the
phenotypical defects caused by single knock-outs. For C-terminal negative regulatory region (173-176), the
example, hck/src-null mice exhibit substantially more SH2/SH3 domains (177-180), or the residues responsible
severe osteopetrosis than src-null mice (151). Likewise, for the interactions between the linker region and the kinase
fyn/lck-null mice show a dramatic further reduction in domain (172). Physiological regulation of Src-family PTKs
thymocyte development as compared to lck-null mice is mediated by modulation of the interactions described
(152). Furthermore, neutrophils of hck/fgr-null mice above achieved by (a) phosphorylation/dephosphorylation
demonstrate susceptibility to Listeria, which is not seen in of the C-terminal regulatory site, and (b) binding of the
single knock-outs (153). Consistent with this finding, SH2 and SH3 domains of Src-family PTKs to various
neutrophils of these double mutants, but not those of the phosphotyrosine- or polyproline-containing proteins.
corresponding single mutants, are impaired in adhesion and
spreading on extracellular matrix (154). Likewise, The C-terminal tyrosine is thought to be
monocytes of the hck/fgr/lyn triple null-mutant mice are phosphorylated primarily by Csk-family PTKs (181-188)
defective in adhesion and spreading (155). Finally, many of and dephosphorylated by several protein tyrosine
the double mutations, such as src/fyn-null and src/yes-null, phosphatases (PTPs), including CD45 (189-195), PTP-
are lethal (reviewed in (150)). alpha and -lambda (196-198). Although it is clear that the
removal of a phosphate from the autophosphorylation site
should inhibit Src-family PTK activity, the nature of PTPs
The kinase activity of Src-family PTKs is involved in this process is less clear. PEP and SHP-1 PTPs
regulated by their tyrosine phosphorylation. There are two are possible candidate for this role (199-202).
major tyrosine phosphorylation sites in Src-family PTKs,
the autophosphorylation site and the C-terminal negative Binding of the SH2 and SH3 domains of Src-
regulatory site, corresponding to tyrosines 419 and 530 of family PTKs to phosphotyrosine- or polyproline-containing
human Src. Autophosphorylation of Src-family PTKs ligands may disrupt the intramolecular interactions of Src-
appears to be an intermolecular process (156-158). family PTKs that negatively regulate Src-family PTKs and,

598
Non-receptor protein tyrosine kinases

hence, activate these kinases. For example, phosphorylated The main function of Csk-family PTKs appears
forms of PDGF receptor (203), Cas adaptor protein (204) to be the negative regulation of Src-family PTKs mediated
and Fak (124, 125) activate Src-family PTKs by binding to by phosphorylation of their inhibitory tyrosine residue,
their SH2 domains. Similarly, several proteins, including which has been shown in multiple experimental systems
the HIV protein Nef, activate Src-family PTKs by binding (225-229). Consistent with this notion, the C-terminal
to their SH3 domains (205-207). Furthermore, interactions regulatory domain of full-length Src-family PTKs is the
of Src-family PTKs with protein ligands may cause most catalytically efficient substrate known to date (230),
translocation of the former to the sites of action. Such although CD45 also appears to be phosphorylated by Csk
interactions include above-mentioned binding of Src-family (231). Phosphorylation of CD45 by Csk activates CD45
PTKs to various cell surface receptors, proteins of the and creates on it an Lck-binding site.
cytoskeleton and adhesion complexes and nuclear proteins.
The targeted disruption of csk has confirmed that
Other phosphorylation sites have also been Csk plays a crucial regulatory role, since csk-null embryos
identified on Src-family PTKs. Several serine residues are die due, apparently, to a defect in the neural tube (185,
phosphorylated within the unique domain of Lck upon 232). Cells derived from these embryos exhibit a dramatic
TCR- or IL-2-dependent stimulation, as well as PMA increase in the kinase activity of Src, Fyn and Lyn (185,
treatment. This phosphorylation, most likely mediated by 232). Furthermore, the generation of chimeric mice using
Erk kinases, does not seem to substantially affect Lck csk-null embryonic stem cells has shown that T- and B-cell
kinase activity, although it has been proposed that it might differentiation of csk-null progenitors is blocked at very
work as a negative feedback (208-213). In contrast, serine early stages, whereas the development of myelomonocytic
phosphorylation of the unique domain of Src by PKA has cells remains normal (233). It is important to note that
recently been shown to activate this PTK (214). activation of either Lck or Fyn does not block lymphoid
differentiation, as it is seen in csk-null cells (141, 233).
Furthermore, sites of tyrosine phosphorylation This finding indicates that Csk, in addition to its
have been identified within the SH2 domains of Lck and generalized functions related to the inhibition of Src-family
Src (215-217) and within the SH3 domain of Src (218). PTKs, may have specific functions in lymphoid cells that
Phosphorylation of these sites may disrupt SH2- and SH3- are mediated by other targets of Csk.
mediated interactions of Src-family PTKs with their protein
ligands. In contrast, matk-null mice are viable, exhibiting no
significant abnormalities (234). Furthermore, kinase activity of
Finally, the activity of Src-family PTKs has been Src-family PTKs remains unchanged in bone marrow cells of
shown to be regulated by ubiquitylation-induced matk-null mice (234). This finding indicates a high degree of
degradation of their activated forms (219-222). In some redundancy between Csk and Matk and points to the difference
cases, this degradation has been shown to be dependent on in their functions. These differences have also been observed
c-Cbl, an E3 ubiquitin ligase capable of interacting with in other experimental systems. For instance, Csk, but not Matk,
Src-family PTKs (221, 222). is capable of inhibiting antigen-induced signaling in T cells
(235), whereas Matk, but not Csk, can bind to TrkA, a nerve
3.2. Csk growth factor receptor PTK, and upregulate neurite outgrowth
The Csk family of PTKs has two members, Csk of PC12 cells (236).
and Matk. The latter is also known as Ctk, Ntk, Chk, Hyl
and Lsk. Csk is expressed ubiquitously, but predominantly In contrast to the Src-family PTKs, the kinase
in thymus and spleen, while Matk is expressed primarily in activity of Csk-family PTKs is not regulated by tyrosine
brain and hematopoietic cells (reviewed in (223)). phosphorylation, consistent with the lack of the respective
phosphorylation sites. It appears, instead, that Csk is activated
Amino acid sequences of Csk- and Src-family as a result of phosphorylation of its Ser-364 by cAMP-
PTKs are highly homologous. The domain structure of dependent protein kinase (PKA) (237). The cAMP-induced
Csk-family PTKs includes an SH3 domain, followed by an activation of Csk may be a key mechanism for the immune cell
SH2 domain and then by a tyrosine kinase domain, and suppression caused by cAMP (238-244). Furthermore, the Csk
therefore, closely resembles that of Src-family PTKs. activation loop itself contains a few putative serine and
Moreover, the crystal structure of Csk is very similar to threonine phosphorylation sites, but there is no evidence of
those of Src-family PTKs (224). However, there are several their phosphorylation.
important points of divergence between Src- and Csk-
family PTKs. First, Csk-family PTKs lack the N-terminal The lack of the C-terminal negative regulatory
unique domain carrying fatty-acid modification sites, which tyrosine in Csk-family PTKs rules out the inhibitory
anchors Src-family PTKs in the membrane. Likewise, the intramolecular interaction of the phosphorylated form of this
C-terminal regulatory site is absent from Csk-family PTKs. tyrosine with the SH2 domain. In contrast, it appears that the
Furthermore, there is no tyrosine residue in the activation intramolecular interaction between the catalytic domain and
loop of Csk. In agreement with this feature, Csk is the SH3 domain of Csk is important for efficient catalysis
incapable of autophosphorylation (see (223)). Because of (245).
the lack of these important tyrosine residues, regulation
mechanisms for Src- and Csk-families of PTKs are very Although intermolecular interactions regulating
different (see below). the activity of Csk-family PTKs are less studied than those

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Non-receptor protein tyrosine kinases

regulating Src-family PTKs, it has been shown that the PTK in activated cells (288). This specific feature of Syk
transmembrane protein PAG/Cbp, which is constitutively may, at least in part, be caused by the higher
phosphorylated on tyrosine, binds to the SH2 domain of conformational flexibility and structural independence of
Csk in T cells. PAG/Cbp is localized to the lipid rafts and the SH2 domains of Syk as compared to those of Zap (290),
thus anchors Csk to these membrane domains, where Csk which is likely to result in a higher flexibility of Syk
may phosphorylate and, hence, inhibit Src-family PTKs. binding to various phosphorylated motifs and a less
TCR stimulation induces transient dephosphorylation of stringent dependence of this binding on the double
PAG/Cbp and dissociation of Csk. Gradually, Csk re- phosphorylation of ITAMs. The differential ability of Zap
associates with PAG/Cbp and returns to the lipid rafts, thus and Syk to bind to doubly phosphorylated ITAMs is also
abrogating the activity of Src-family PTKs (246, 247). related to the structure of their linker region between the
tandem SH2 domains and the kinase domain, which is
3.3. Syk frequently referred to as interdomain B. The prevalent
The Syk family has two members, Syk and Zap- splice form of Syk contains a 23-amino acid insert in this
70. Syk is expressed ubiquitously, including all types of region, which is not found in Zap or a less abundant splice
hematopoietic cells, fibroblasts, epithelial and endothelial form of Syk, SykB (291). The presence of this insert clearly
cells, hepatocytes, and neurons, whereas Zap has been correlates with a higher ability to bind to phosphorylated
found exclusively in T and NK cells (reviewed in (248- ITAMs and to transduce signals from ITAM-bearing
250)). receptors (292), although mechanisms mediating the effects
of this insert remain unclear.
The common structure of Syk and Zap includes
the two SH2 domains located in tandem in its N-terminal The described differences between Syk and Zap
half, which are followed by a catalytic domain. Syk-family are likely to be linked to their distinct biological functions.
PTKs possess no fatty-acid modification sites, which are First, Zap is regulated more stringently than Syk is.
characteristic for Src-family PTKs, and are, as a result, Whereas binding of Zap to ITAMs and its activation are
predominantly cytosolic proteins. However, their strictly dependent on prior stimulation of Src-family PTKs
localization is dramatically affected by cell stimulation. in response to receptor ligation, Syk appears to be able to
The tandem SH2 domains of Syk-family PTKs demonstrate phosphorylate ITAMs and induce signal transduction in the
an extremely high degree of affinity to doubly absence of help from Src-family PTK (see above).
phosphorylated ITAMs, which dramatically exceeds that of Therefore, the functions of Syk show some similarities to
single SH2 domains, including the SH2 domains of Syk those of Src-family PTKs. Indeed, Syk, but not Zap, can
and Zap, to single phosphotyrosine residues (251-253). reconstitute T-cell signaling disrupted by the absence of
Therefore, phosphorylation of ITAMs by Src-family PTK, Lck (293). Likewise, Syk can mediate T-cell signaling in
which represents one of the initial signaling events for the absence of TCR ligation, whereas Zap requires TCR
multiple receptors (see above), generates an excellent ligation to induce signaling (294).
binding platform for Syk-family PTKs. As a result of this
binding, cytosolic molecules of Zap and Syk become Furthermore, Zap appears to be exclusively a
translocated to the cytoplasmic tails of MIRRs in the close lymphoid kinase, whereas Syk is expressed ubiquitously
proximity of the membrane (254-258). This event is critical and the list of its functions outside the lymphoid and even
in signal transduction involving Syk-family PTKs, since its hematopoietic tissue is constantly expanding (250). An
disruption inhibits further signaling (259-261). interesting example of a non-hematopoietic function of Syk
is provided by its participation as a tumor suppressing
Upon recruitment, Syk-family PTKs protein in the development of breast cancer (295).
phosphorylate multiple downstream targets (262-275). Two
major mechanisms appear to activate Syk-family PTKs The results of studies using targeted disruption of
upon their recruitment to ITAM-containing receptors. First, zap and syk genes are consistent with the findings described
phosphorylation of both Syk and Zap by Src-family PTKs above. Mice lacking Zap show a deficiency localized
can activate them (276-280). Several lines of evidence specifically to the T-cell lineage, they have no mature T cells
indicate that this mechanism is more important for Zap than (296, 297). NK cells, which also express Zap in wild-type
for Syk, since Syk can be activated and function in a Src- animals, are not affected by Zap deficiency (296). In contrast,
family PTK-independent manner (281-284). This disruption of syk induces multiple defects, including severe
difference is likely to be due to the ability of Syk to hemorrhaging, that result in embryonic lethality (298, 299). In
phosphorylate ITAMs under certain experimental addition to this, Syk deficiency impairs development of
conditions (284), which is apparently lacked by Zap. The various hematopoietic cells, including B cells (298-300). This
substantially higher intrinsic enzymatic activity of Syk as effect of Syk deficiency on B-cell development is consistent
compared to Zap (285) may also contribute to its relative with the critical role of Syk in BCR-induced signaling (75,
independence of Src-family PTKs. 257, 259, 276, 301).

In contrast, the second mechanism of activation Although Syk can mediate TCR-induced signaling
of Syk-family PTKs is specific for Syk, which, unlike Zap, in multiple experimental systems (see above), and its forced
can be directly activated by binding to a doubly overexpression can rescue T-cell development in Zap-negative
phosphorylated ITAM (284, 286-289). This binding causes animals (302), it is not essential for T-cell development
conformational changes in Syk similar to those seen in this (reviewed in (303)). The lack of effect of Syk on T-cell

600
Non-receptor protein tyrosine kinases

maturation is likely due to a dramatic decrease in its level early ability to be activated by Lck (this activation is
in T-cell development (304). approximately 10-fold for wild-type Zap) and to induce
antigen receptor-mediated signaling and biological
The kinase activity of Syk-family PTKs, like that responses in lymphocytes (277, 278, 312). In contrast, the
of Src-family PTKs, is regulated by their tyrosine Y492F mutation increases basal activity of Zap (277) and
phosphorylation. However, unlike Src-family PTKs, Zap its ability to induce antigen receptor-mediated signaling
and Syk have a large number of tyrosine phosphorylation and responses (312). Hence, Tyr-492 and -493 play in the
sites that affect the functions of these PTKs in various activation of Zap a negative and a positive regulatory role,
ways. respectively.

The primary autophosphorylation sites of Zap In contrast to phosphorylation of tyrosines 492

appear to be the three residues located in the interdomain and 493 of Zap by Lck, the corresponding tyrosines 525
B, tyrosines 292, 315 and 319 (human sequences are used and 526 of Syk are autophosphorylated (307, 308).
for numbering residues in Zap and Syk) (305, 306), Although consequences of phosphorylation of Tyr-525 and
corresponding to tyrosines 323, 348 and 352 of human Syk, -526 of Syk are less studied than those for Tyr-492 and -
which are also autophosphorylated (307, 308). 493 of Zap, it appears that their phosphorylation is unlikely
Furthermore, these sites in Syk can be phosphorylated by to significantly affect the intrinsic kinase activity of Syk
Lyn, a Src-family PTK (308). Phosphorylation of the (267, 322, 323). Despite the lack of this effect, the
interdomain B sites is not essential for kinase activity of autophosphorylation sites of Syk are required for Syk-
either Zap or Syk (267, 309, 310), playing instead an mediated signal transduction and biological responses (259,
important regulatory role. 267, 322-324). The essential role of Tyr-525/Tyr-526
phosphorylation may be due to binding of proteins that
Cells expressing Y292F mutant Zap or the propagate Syk-mediated signaling, for example, Lck (324).
analogous Y323F Syk demonstrate hyperactive signal
transduction and biological responses to TCR, BCR and C-terminal tyrosines 629, 630 and 631 of Syk
FcepsilonRI receptor ligation (308, 311-314). Therefore, have been shown to be autophosphorylated (307, 308).
Tyr-292 of Zap/Tyr-323 of Syk is a major negative Mutation of these tyrosines or of those corresponding to
regulatory site. The mechanism of this negative regulation, them in Zap (Tyr-597 and –598) resulted in the gain-of-
is unlikely to be related to a decrease in the intrinsic function phenotypes of Syk and Zap, as demonstrated by
enzymatic activity of these PTKs (311) and appears to tyrosine phosphorylation of potential targets in vivo,
involve binding of a negative regulator of PTKs, c-Cbl, to elevated intracellular calcium mobilization and promoter
this site (315-317). For Syk, this negative effect of c-Cbl activation (325). These results implicate the C-terminal
has been shown to be dependent on the E3 ubiquitin- tyrosine residues of Syk and Zap as important negative
protein ligase activity of c-Cbl and mediated by regulatory sites. Phosphorylation of these residues, like that
ubiquitylation of the activated form of Syk followed by its of the majority of other tyrosine residues of Syk and Zap,
proteosomal degradation (316, 327, 328). This mechanism does not affect the intrinsic enzymatic activity of these
might also be involved in the c-Cbl-dependent inhibition of PTKs, but reduces their ability to transmit signals.
Zap, although this possibility has not been shown directly.
With the exception of Tyr-292 of Zap/Tyr-323 of
In contrast, phosphorylation of Tyr-319 has a Syk, the mechanisms mediating effects of negative
positive effect on Zap-mediated signaling. First, it appears regulatory tyrosines of Zap and Syk remain unclear.
to mediate interactions of Zap with Lck (306, 318, 319) and However, one may speculate that some of them play their
PLC-gamma1 (319). Furthermore, this site is essential for role by interacting intramolecularly with the SH2 domains
tyrosine phosphorylation of Zap-specific substrates and of the same molecule. Indeed, the deletion of both SH2
multiple downstream signaling events mediated by Zap domains moderately increases enzymatic activity of Zap in
(306, 318-320). vitro and increases its tyrosine phosphorylation in vivo
(309). The deletion of both SH2 domains also abolishes a
The role of Tyr-315 of Zap is not very clear. One lag phase of kinase activity detectable with the full-length
report argues that this residue might be involved in the Zap (326). However, the addition of recombinant SH2
interactions of Zap with Vav and in tyrosine domains to the truncated Zap lacking SH2 domains restored
phosphorylation of Zap-specific substrates (320), but this the lag phase. In contrast, this lag phase can be abolished
has not been seen in the other studies (306, 321). by the addition of a diphosphorylated ITAM peptide (326).

Consistent with the role of Tyr-319 and Tyr-315, 3.4. Tec

phosphorylation of tyrosines 352 and 348 in the linker The Tec family of PTKs has five members, all of
region of Syk is not required for the activity of this PTK, which are present in human and mouse genomes. Tec-
but is essential for its binding to PLC-gamma1 its ability to family PTKs have similar domain structures consisting
phosphorylate PLC-gamma1 in vivo (267). typically of the N-terminal pleckstrin-homology domain
(PH) followed by a Tec-homology domain (TH), which is
Tyrosines 492 and 493 of Zap are major sites of sometimes subdivided into the cystein-rich, Zn2+-binding
its phosphorylation by Lck (305). The Y493F mutation Btk motif and a proline-rich motif. The PH and TH
does not affect basal activity of Zap, but abrogates its domains are followed by SH3, SH2 and kinase domains.

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Two Tec-family kinases are exceptions from this typical be studied in most detail, Tec-family PTKs mediate
structure. First, TH and SH3 domains of Bmx are signaling that leads to the activation of NF-kappaB (375-
significantly modified, so they are sometimes referred to as 377), the Akt kinase (378), Stat transcription factors (379-
TH-like and SH3-like domains (329, 330). Second, Txk 382), Rho-family GTPases (372, 383) and integrins (384).
lacks both PH and TH (331-334), but has, instead, a unique The important role of Tec-family PTKs in signaling is
cystein string motif, which can be palmitoylated (335). supported by the phenotype of deletion and loss-of-function
mutants. It should be noted that the lack of functional Btk
Whereas Bmx and Tec are expressed in multiple causes a severe human disease, X-linked
tissues and cell types, both hematopoietic and non- agammaglobulinemia (XLA) (385, 386). Patients with
hematopoietic, other Tec-family kinases show primarily XLA essentially lack B cells and immunoglobulins. The
hematopoietic distribution. Itk is expressed mainly in T and targeted disruption of Btk in mice is consistent with these
NK cells. Btk is expressed in B lymphocytes and cells of findings, leading to a decrease in the number of B cells and
erythromyeloid lineage. Txk is expressed primarily in T the levels of immunoglobulins, although the phenotype of
and mast cells (reviewed in (330, 336)). btk-null mice is substantially milder than that of XLA
Tec-family PTKs typically lack an acylation site and are, (387). Inactivation of the tec gene does not generate a
therefore, localized in the cytosol in the absence of distinct phenotype, but the double btk/tec-null mutation
stimulation (330, 336). However, they can re-localize to the results in a more severe B-cell phenotype than the single
membrane following cell stimulation, because cell btk knock-out, which is still milder than the XLA
stimulation typically causes activation of PI-3’ kinase, phenotype (388). Inactivation of the itk gene in mice results
producing phosphoinositides containing a phosphate in the in a mild T-cell phenotype characterized by a decrease in
position 3 of their inositol ring, to which a PH domain the numbers of mature T cells and their lower
binds with very high affinity (337-341). Such membrane responsiveness to TCR-mediated stimulation (389). This
localization is highly transient, since these phosphorylated phenotype is exacerbated when txk is also inactivated
lipids are short-lived. Indeed, Btk becomes constitutively (390). The bmx knock-out mice do not demonstrate an
membrane-localized when PTEN, a lipid phosphatase overt phenotype (391).
dephosphorylating PI-3’ kinase products, is defective (342,
343). The functions of Tec-family PTKs are
regulated by several very distinct mechanisms, including
Txk, which has an unusual structure, also shows their tyrosine phosphorylation. It has been shown that
the unusual subcellular distribution. The cystein string- intramolecular interactions between an SH3 domain and
containing palmitoylated form of Txk is membrane- a proline-rich region are likely to yield an inactive
localized. The alternative initiation form of Txk, which conformation in Itk (392). Furthermore, interactions
does not have the cystein string, is localized in the nucleus between these domains of Tec-family PTKs may lead to
(335). Recently, Btk has also been found in the nucleus. dimerization of these kinases (393, 394), which may
Nuclear translocation of Btk is facilitated by the loss of PH also play a negative regulatory role. It is possible that
or SH3 domains (344). Similarly, Itk has been found to the two proline-rich motifs of the proline-rich regions
localize to the nucleus, and this localization is upregulated are differentially involved in intra- and inter-molecular
by TCR ligation (345). It is unclear whether other Tec- interactions with SH3 domains (395). Consistent with
family PTKs can translocate to the nucleus in a similar these findings, a deletion of SH3 constitutively activates
manner. It is however apparent that PH, TH, SH3 and SH2 Tec (396). It is thought that these inhibitory interactions
domains of Tec-family PTKs may regulate their functional are disrupted, when the PH domain of Tec-family PTKs
interactions with multiple proteins (reviewed in (330, binds to phosphoinositides, G-proteins, or other PH
336)). ligands. Furthermore, the association of PH domains of
Tec-family PTKs to phosphoinositides or G-proteins
Tec-family PTKs participate in multiple signaling results in the membrane translocation of these kinases,
pathways. They have been shown to become activated in which appears to be another critical event in their
response to MIRR ligation (346-349) and to mediate physiological activation. Indeed, PI-3’ kinase has been
MIRR-induced signaling that involves adaptor proteins shown to be a critical upstream regulator of Tec-family
BLNK and SLP-76, PLC-gamma, Ca2+ mobilization and PTKs in multiple systems (362 , 371, 397-400). In
Ca2+-induced events (350-362). Itk and Tec are also agreement with these findings, the constitutive
activated by the ligation of CD28, an important T-cell co- production of PH-binding lipid products of PI-3’ kinase
receptor molecule (363, 364). This activation leads to in PTEN-deficient cells (343), as well as the
multiple downstream effects, which are specific for modification of Tec-family PTKs with a membrane-
individual PTKs. These effects include activation of PLC- interactive site (401, 402), activates Tec-family PTKs
gamma, Ca2+ mobilization, and activation of IL-2 and IL-4 and facilitates signaling mediated by them. In addition,
promoters (355, 364-367). Tec-family PTKs have also been the adaptor protein Lat and Zap, a PTK that
shown to become activated through various cytokine phosphorylates Lat in T cells, have been shown to be
receptors (368-371), G protein-coupled receptors (372, essential for the activation of Itk in T cells (273, 274).
373) and integrins (373, 374). Binding of the SH2 domain of Itk to tyrosine
phosphorylated Lat appears to mediate the effect of Lat
In addition to the triggering of Ca2+-mediated on Itk activation (274). Similarly, BLNK appears to
signaling in response to MIRR ligation, which appears to mediate activation of Btk by Syk (275).

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The membrane translocation of Tec-family PTKs 444), reviewed in (409, 410)). Stat-family proteins become
facilitates phosphorylation of the activation loop tyrosine phosphorylated on tyrosine following their binding to the
residue in these kinases, this tyrosine is homologous to Tyr- receptors, form homo- or heterodimers mediated by
419 of human Src (Tyr-551 and -517 in human Btk and Itk, phosphotyrosine-SH2 interactions, relocate to the nucleus
respectively), and its phosphorylation activates Tec-family and activate transcription controlled by the corresponding
PTKs (349, 403-407). This activation results in DNA elements (reviewed in (445-447)). Although Jak-
autophosphorylation of Tyr-223 (numbering for Btk) within family PTKs are, to a certain degree, capable of
the SH3 domain, which disrupts the inhibitory interactions phosphorylating Stat’s, it appears that Stat’s are tyrosine-
between the SH3 domain and the TH domain proline-rich phosphorylated primarily by Src-family PTKs (105, 448),
region, thus further enhancing protein phosphorylation by whereas the major role of Jak-family PTKs appears to be
Tec-family PTKs (408). the generation of docking sites for Stat’s and, possibly, Src-
family PTKs on the corresponding receptors.
3.5. Jak
The Jak (or Janus) family of PTKs has four The crucial role of Jak-family PTKs in cell
members, all of which are present in human and mouse signaling is supported by the phenotype of the Jak-negative
genomes. Jak-family PTKs differ markedly from other mice. The targeted disruption of Jak1 or Jak2 is lethal (449-
PTKs by the presence of two kinase domains, which are 451). Jak3-deficient mice are viable, but immunodeficient,
both located in the C-terminal half on the molecule. Only exhibiting profound defects of lymphoid cell development
the C-terminal-most domain is functional, the other one (452-454). These defects drive, in turn, hyperexpansion of
thus being a pseudokinase domain (reviewed in (409, 410)). myeloid lineage (455). Furthermore, mutations in Jak3 that
The N-terminal region of Jak-family PTKs contains several disrupt normal Jak3-mediated signaling have been found in
highly conserved sequence stretches, which were originally several patients with autosomal severe combined
termed JH domains (reviewed in (409)). It has been shown immunodeficiency (425, 456).
recently that some of these sequences represent the FERM
(see Section 3.6) and SH2 domains of Jak-family PTKs. The functions of Jak-family PTKs are regulated
by several distinct mechanisms. Receptor-mediated
Jak-family PTKs lack an acylation site and, activation of a Jak-family PTK is induced by tyrosine
hence, are localized in the cytosol in the absence of phosphorylation of its activation loop as a result of its
stimulation. However, these PTKs are bound to multiple auto(trans)phosphorylation or phosphorylation by other
membrane receptors in the absence of stimulation and, in PTKs that may or may not belong to the Jak family. Two
many cases, additionally recruited to these receptors adjacent tyrosine residues become phosphorylated in the
following their ligation ((411-419), reviewed in (409, activated loop of several Jak-family PTKs. Phosphorylation
410)). This binding is mediated by the N-terminal region of of these tyrosines, especially that of the more N-terminally
Jak PTKs (420-425). The interactions of Jak-family PTKs located one, appears to be required for a ligand-induced
and membrane receptors play a crucial role in the increase in the activity of Jak-family PTKs (457-459).
biological function of these PTKs, which mediate signaling
induced by most interleukins, all interferons, and multiple The tyrosine phosphorylation-mediated activation
other cytokines and colony-stimulating factors, as well as of Jak-family PTKs is negatively regulated by several
by some growth factors and hormones. Tyk2, Jak1 and protein-tyrosine phosphatases, such as SHP-1 and -2, SH-
Jak2 mediate signaling through a wide variety of receptors, PTP1, SHPeC, and TC-PTP (460-466). Interactions of Jak-
whereas the involvement of Jak3 is more specific, it is family PTKs with these phosphatases may be mediated by
involved in signaling induced by IL-2, IL-4, IL-7, IL-15 their direct binding independent of SH2 or
and G-CSF ((411-416, 426-428, 429 9486, 430-444), phosphotyrosines or by the recruitment of these
reviewed in (409, 410)). phosphatases to the corresponding receptors
phosphorylated on tyrosine by Jak-family PTKs. The latter
The specificity of the involvement of Jak-family mechanism may represent a negative feedback loop that
PTKs in receptor-mediated signaling is also reflected in rapidly dampens an increase in Jak-family PTK activity.
their expression pattern. Tyk2, Jak1 and Jak2 are expressed
ubiquitously, whereas Jak3 is expressed primarily, although Furthermore, Jak-family PTKs appear to be
not exclusively, in hematopoietic cells (reviewed in (409, negatively regulated by proteosome-mediated degradation
410)). in a manner similar to that of Src- and Syk-family PTKs
(467, 468). However, this regulatory mechanism is less
The involvement of Jak-family PTKs in receptor- studied for Jak-family PTKs than for those of Src and Syk
mediated signaling is due to their binding to the families.
corresponding receptors and their further recruitment to
these receptors following ligation of the latter. The Another negative feedback loop that regulates
recruitment of Jak-family PTKs to the corresponding Jak-mediated signaling appears to be specific for these
receptors appears to result in their tyrosine phosphorylation signaling pathways. Jak-mediated activation of Stat’s
and activation, which results, in turn, in specific tyrosine induces expression of multiple genes, including those
phosphorylation of these receptors that generates docking encoding for small SH2-containing proteins referred to as
sites for Stat-family transcription factors and other SH2- COCS, CIS, SIS or JAB (reviewed in (409, 469, 470)).
containing proteins ((411-416, 427, 429 9486, 430-442, Different proteins of this family negatively regulate Jak-

603
Non-receptor protein tyrosine kinases

mediated signaling by various mechanisms, including has been well documented that Fak plays a critical role in
binding to the tyrosine phosphorylated receptors that blocks cell migration (reviewed in (498, 499)). These functions are
recruitment of signaling molecules to these receptors and naturally linked, since the focal adhesion turnover is
binding to the phosphorylated activation loop of Jak-family essential for cell migration. Other possible functions of Fak
PTKs that directly inhibit their catalytic activity. include positive regulation of cell cycle (504) and survival
(505-507).
3.6. Fak
The Fak family of PTKs has two members, both Unlike Fak, Pyk2 can be activated in a Ca2+-
of which are present in human and mouse genomes. Fak, dependent fashion by multiple stimuli that elevate the
the prototypical family member, is expressed ubiquitously, intracellular level of free Ca2+, as well as by some stress
whereas the second PTK of this family, referred to as Pyk2, signals. Activation of Pyk2 results in triggering several
Cak-beta, Cadtk, Raftk, or Fak2, is primarily expressed in signaling pathways, including the MAP kinase cascade.
brain and, to a lower extent, in liver, lung, kidney and The ability of Pyk2 to respond to Ca2+ facilitates its
hematopoietic cells (471-478). function as a link between heterotrimeric G protein-coupled
receptors and downstream signaling pathways, such as the
The catalytic domain of Fak-family PTKs is MAP kinase cascade (reviewed in (508, 509)) and the I-
flanked with extensive N- and C-terminal sequences. The kappaB/NF-kappaB system (510). Furthermore, in some
N-terminal region of Fak-family PTKs contains the FERM cases Pyk2 may act opposite to Fak, as it happens in the
domain, which is also present in talin and other cytoskeletal regulation of cell cycle progression, which is promoted by
proteins and is capable of mediating interactions of these Fak, but inhibited by Pyk2 (511). Biological functions of
proteins with transmembrane receptors. It is possible that Pyk2 remain to be characterized further. Considering that
the FERM domain of Fak mediates the interactions of Fak Pyk2 is most abundantly expressed in the brain, its recently
with integrins and/or receptor PTKs (479-482). The C- described roles in neuronal differentiation (512) and the
terminal region of Fak-family PTKs also possesses a region development of long-term potentiation in neurons (513)
implicated to focal adhesion targeting of Fak (FAT domain) appear to be important.
(483-485). It is possible that the FAT-dependent targeting
of Fak to focal adhesions is mediated, at least partially, by In spite of these differences, Pyk2 and Fak
paxillin (483, 486, 487). Talin was also proposed as a phosphorylate a common set of proteins including tensin,
mediator of this targeting (488). Finally, the C-terminal paxillin, and Cas (495), and their functions appear to be
region of Fak-family PTKs contains two SH3-binding sites. redundant to some extent. Thus, tyrosine phosphorylation
These sites mediate binding of Fak and Pyk2 to several of Pyk2 was enhanced by integrin stimulation in Fak-
proteins, including Cas, which is likely to be important for deficient cells (514, 515). Furthermore, Pyk2 enhanced
their functions (489-492). Interestingly, two alternatively adhesion-stimulated activation of Erk in Fak-deficient cells
spliced isoforms of Pyk2 specific for either hematopoietic (515). Finally, although wild-type Pyk2 did not restore
cells or the brain have been described that differ by the normal migration of Fak-deficient cells (496, 515), an
presence of an insert between the SH3-binding sites (493, engineered form of Pyk2 capable of binding to focal
494). contacts could reconstitute it fully (496).

Although both Fak and Pyk2 contain the FERM Fak-deficiency is embryonic-lethal in mice (501)
and FAT domains and in spite of the fact that Fak and Pyk2 due to profound developmental abnormalities similar to
bind to several identical proteins, their subcellular those caused by the lack of fibronectin (516). Cells
localization is different. Whereas Fak can localize to focal obtained from Fak-deficient mouse embryos demonstrated
adhesions, the localization of Pyk2 is diffuse. This is a significant decrease in motility (501, 517). In contrast,
unlikely to be a reflection of the intrinsic inability of the Pyk2-null mice are viable, although B-cell development in
corresponding Pyk2 domains to interact with focal these mice is defective (518)
adhesions (488, 493, 495, 496), but might be caused by the
specific cytoplasmic interactions of Pyk2. Some results also The regulation of Fak functional activity is
argue that the ability of Pyk2 to reorganize the cytoskeleton primarily mediated by tyrosine phosphorylation. It appears
is inhibited in vivo by Fak (497). that the tyrosine residue of Fak phosphorylated upon
integrin stimulation is its major autophosphorylation site,
The differences in subcellular localization of Fak Tyr-397 (120, 125, 519, 520). This tyrosine is located
and Pyk2 correspond to the differences in their functions. outside the kinase domain and is, in its phosphorylated
Fak is activated following integrin stimulation through a form, a docking site for the SH2 domains of several
mechanism requiring the focal adhesion targeting of Fak proteins, including Src-family PTKs (125, 521-523). Upon
and apparently involving Rho as an upstream signaling binding to Fak, Src-family PTKs phosphorylate tyrosines
element (reviewed in (498, 499)). Activation of Fak 576 and 577 inside the activation loop of the catalytic
appears to trigger multiple signaling pathways, including domain of Fak, thus enhancing the kinase activity of Fak to
the MAP kinase cascade (reviewed in (498-500)). The its maximal level (520). In addition, several other sites of
major biological function of Fak signaling is likely to be tyrosine phosphorylation have been identified (Tyr-407, -
the regulation of disassembly of focal adhesions (501-503). 861, -925) (520, 524, 525). These phosphotyrosines are
It is possible that this effect of Fak is due to the Fak- likely to act as docking sites for Fak-binding proteins.
dependent inhibition of Rho GTPase (503). Furthermore, it Thus, phosphorylated Tyr-925 has been shown to bind to

604
Non-receptor protein tyrosine kinases

Grb2 (524, 525). Sites corresponding to four of the high sequence similarity to Abl within the N-terminal
identified sites are also phosphorylated in Pyk2, whereas region encompassing SH3, SH2 and kinase domains (over
Tyr-407 and -861 sites appear to be unique for Fak (526). 90%), but only moderate within the C-terminal region
Furthermore, Pyk2 appears to be phosphorylated on (29% overall), with 56% in the last 60 amino acids (540).
tyrosines other than the four currently identified sites (527). Some critical elements of structure, such as the SH3-
Finally, four serine phosphorylation sites have been binding sites and the actin-binding domain, are conserved
mapped to the C-terminal domain of Fak. Some of these in Arg (549, 550). Furthermore, both Abl and Arg genes
sites are hyperphosphorylated during mitosis, and this contain two alternative 5’ exons, generating two variant
hyperphosphorylation correlates with a decrease in Fak proteins referred to as 1a and 1b. The latter contains an N-
activity (528). myristoylation site similar to that in Src-family PTKs,
which enables it to localize to the membrane (reviewed in
The events that triggers activation of Pyk2 are (548, 551)).
very different from those of Fak, Pyk2 is positively
regulated by Ca2+ and, therefore, activated by a variety of Localization of Abl is complex and is regulated
stimuli that elevate the intracellular level of free Ca2+ by multiple elements of its structure. The majority of cell
(reviewed in (509)). It should be noted that in spite of the types demonstrate predominant localization of Abl to the
ability of Pyk2 to respond to Ca2+, its activation requires nucleus with a significant amount of it present also in the
the intact actin cytoskeleton (reviewed in (509)). This cytoplasm, where much of Abl is bound to the membranes
connection may be due to the ability of Rho to regulate and actin filaments. In hematopoietic cells and neurons Abl
Pyk2 in an F-actin-dependent fashion (529). is predominantly cytoplasmic. Arg appears to be
exclusively cytoplasmic ((544, 552-555), reviewed in (547,
Multiple protein tyrosine phosphatases, including 548, 551)). Nuclear localization of Abl is controlled by its
Shp-2 and PTP1B, may be involved in the negative NLS and NES sites (556, 557). Membrane localization of
regulatation of Fak. Furthermore, PTEN, a phosphatase Abl is dependent on a myristoylation site (558, 559),
better known for its lipid dephosphorylation activity, has whereas Abl association with the actin cytoskeleton is
been implicated in the negative regulation of Fak (reviewed mediated primarily by its actin-binding domain (560, 561).
in (499)). Protein tyrosine phosphatases are likely to be The cytoplasmic localization of Arg is similar to that of
involved in the regulation of Pyk2, as well (530, 531). Abl. First, the splice isoform 1b of Arg possesses the N-
Negative regulation of both Fak and Pyk2 may also be myristoylation site (555). Second, Abl and Arg have been
mediated by the FIP200 protein, which can bind to these shown to co-localize with each other and with the actin
PTKs and inhibit their catalytic activity in vitro (532). filaments (544). The subcellular localization of Abl appears
to be dynamic. Thus, Abl demonstrates transient re-
Finally, negative regulation of Fak and Pyk2 may localization from the nucleus to focal adhesions upon re-
be mediated by an unusual mechanism based on the attachment of suspended fibroblasts (562).
autonomous expression of their C-terminal domains,
referred to as Frnk and Prnk (Fak- and Pyk2-related non- The characteristic subcellular localization pattern
kinases) (493, 533). Frnk is a translation product of the of Abl argues that it may be involved in the regulation of
specific mRNA that is transcribed from the alternate cellular processes associated with the nucleus (reviewed in
promoter located inside the genes encoding for Fak (534). (547)). Thus, Abl has been implicated in transcription
The effects of Frnk and Prnk in several experimental based on its ability to phosphorylate the C-terminal domain
systems (493, 535-537) suggest that they may function as of RNA polymerase II (563, 564) and to interact with
natural inhibitors of the corresponding PTKs. several proteins known to regulate transcription, such as
p53 (565). Furthermore, several studies have argued that
3.7. Abl Abl participates in the signaling pathway, which is induced
The Abl family of PTKs consists of two by DNA damage and regulates DNA recombination and
members, Abl and Arg, both of which are present in human repair (566-569). Furthermore, it has also been proposed
and mouse genomes and are expressed ubiquitously with that Abl is involved in the cell cycle through its ability to
the highest levels detected in the thymus, spleen and testes negatively regulate the G1/S transition (556, 565, 570-574).
for Abl and in the brain for Arg (538-545). Finally, Abl may be involved in the regulation of apoptosis.
The evidence has been presented to support both a pro-
The structure of Abl, a prototypical member of apoptotic (573-575) and anti-apoptotic role (576) for Abl. It
the Abl family, is similar to that of Src-family PTKs within is not clear whether Arg plays any role in the nucleus,
its N-terminal region, which includes one SH3, one SH2, because it appears to localize to the cytoplasm. However, it
and one tyrosine kinase domain. Unlike Src-family PTKs, has been shown that Arg, like Abl, can phosphorylate the
Abl has no C-terminal negative regulatory site, but instead C-terminal domain of RNA polymerase II (577).
possesses a large C-terminal region containing multiple
functional sites. Immediately following the kinase domain In the cytoplasm, the majority of Abl is
is a proline-rich region followed by a DNA-binding associated with the actin cytoskeleton through its C-
domain. The most C-terminal portion of Abl is an actin- terminal actin-binding domain (560, 561). Furthermore, re-
binding domain. The C-terminal region contains three attachment of trypsinized fibroblasts causes transient
nuclear localization signals (NLS) and one nuclear export activation of Abl and its translocation to focal adhesions
signal (NES) (reviewed in (546-548)). Arg demonstrates a (562), as well as its binding to paxillin, which is a substrate

605
Non-receptor protein tyrosine kinases

of Abl and a major component of focal adhesions (578). kinase activities between wild-type c-Abl and deregulated
These findings argue that Abl is involved in the oncogenic forms of Abl reported in several studies (558,
cytoskeleton regulation. This involvement may be mediated 587, 588) argued in favor of the intermolecular mechanism.
by the adaptor protein Crk, whose protein-binding activity Several Abl-binding proteins, such as 3BP1, 3BP2, Aap1,
is negatively regulated by Abl (579), it has been shown that Abi-1, Abi-2, and Pag, have been implicated in the
Abl disrupts interactions of Crk with paxillin and Cas and, regulation of Abl activity, but their roles in this
as a consequence, affects cell adhesion and migration (580, phenomenon remain to be elucidated ((589-594), reviewed
581). Another possible target of Abl involved in the in (548)).
regulation of cytoskeleton rearrangements and cellular
morphogenesis is delta-catenin, a potent substrate of Abl The recent findings indicating significant
(582). The effects of Abl on the cytoskeleton and differences in kinase activity in vitro between wild-type
morphogenesis appear to be induced not only by integrins, Abl and its constitutively active forms (595, 596) argued
but also by various receptor PTKs (580, 583, 584). The last that the Abl SH3 domain can inhibit Abl kinase activity
of these studies indicated considerable similarities between through an intramolecular interaction. Further studies
the interactions of Abl and Arg with Eph receptor PTKs. argued that this interaction is likely to be mediated by the
Although little is known about the functions of Arg as proline-rich linker region of Abl located between its SH2
compared to Abl, these results, as well as those obtained and kinase domains (597).
using cells lacking Abl and Arg (see below), suggest that
some functions of these PTKs overlap. Tyrosine phosphorylation of Abl, like that of
other PTKs, appears to play an important role in its
Finally, it should be noted that all deregulated enzymatic activation. Autophosphorylation of Abl on
oncogenic forms of Abl, such as v-Abl and Bcr-Abl, tyrosine 412 in the activation loop significantly increases
causing cell transformation in experimental and real its kinase activity (595). Some role in Abl activation, albeit
pathological situations, are cytoplasmic (reviewed in a weaker one than that of Tyr-412, is played by Tyr-245
(551)). These findings further support the importance of located inside the linker region between the SH2 and kinase
cytoplasmic c-Abl for cell activation and argue that its domains (595). The autophosphorylation of Abl is
functions are unlikely to be restricted to the cytoskeletal concentration-dependent (595) indicating its intermolecular
regulation. nature, when Abl molecules phosphorylate each other. The
phosphorylation of the positive-regulatory Tyr-412 can be
Targeted disruptions of Abl-family PTK genes achieved not only by Abl itself, but also by heterologous
confirmed their biological importance and outlined their PTKs, such as Src (583).
specific biological functions. The loss of Abl is lethal, and
many abl-null mice show thymic and splenic atrophy and 3.8. Fes
T- and B-cell lymphopenia (542). Furthermore, mice The Fes family of PTKs has two members, Fes
homozygous for the mutant form of Abl lacking the C- (also referred to as Fps) and Fer, which are present in both
terminal region demonstrate a very similar phenotype, human and mouse genomes. The members of this family
including the increased perinatal mortality and abnormal are highly homologous and consist of an N-terminal FCH
spleen and B-cell development (585). (This study provides domain followed by three coiled-coil regions, an SH2
evidence not only for the importance of Abl, but also domain in the central part of the protein, and a kinase
argues that the C-terminal region is essential for the domain in the C-terminal region (reviewed in (598, 599)).
biological functions of Abl.) In contrast, arg-null mice Fes is highly expressed in cells of the myeloid lineage, but
developed normally, but exhibited multiple behavioral also in endothelial, epithelial and neuronal cells (600-604).
abnormalities (544). Deficiency in both Arg and Abl Fer is expressed ubiquitously (605).
resulted in embryonic lethality, which was associated with
profound alterations of the actin cytoskeleton in arg/abl- Fes-family PTKs lack any membrane-attachment
null cells (544). sites and are localized primarily to the cytosolic fraction
(604, 606, 607). Furthermore, it has been shown that a
The model of Abl-family regulation is based on substantial fraction of Fes is localized to the trans-Golgi
Abl, a prototypical family member, since little is known vesicular network (604, 607). Binding of Fes to
about the regulation of Arg. A characteristic feature of Abl cytoskeletal components, including Cas, has also been
regulation is that in vivo its wild-type form is not tyrosine- shown (608), suggesting that Fes may be associated with
phosphorylated and induces no tyrosine phosphorylation of the cytoskeletal structures. The FCH domain of Fes-family
other proteins under non-stimulated conditions (558, 586, PTKs is capable of binding to tubulin (reviewed in (599)),
587). This tight regulation appears to be mediated by the thus further arguing in favor of the possible cytoskletal
SH3 domain of Abl, since mutations affecting this domain localization of Fes-family PTKs. Nuclear localization of
resulted in an increase in Abl kinase activity in vivo and its Fes and Fer was also reported (609, 610), but this
transformation potential (558, 586-588). It is not entirely observation could be an artifact related to their perinuclear
clear whether the Abl SH3 domain down-regulates the localization to the trans-Golgi network.
activity of Abl because of intermolecular interactions with
SH3-binding inhibitor proteins acting in trans, or because Multiple retroviral oncogenes contain Fes and Fer
of intramolecular interactions of this domain with SH3- sequences, and activated forms of Fes and Fer can mediate
binding sites of Abl. The lack of a difference in in vitro cellular transformation (reviewed in (598, 599)). These

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findings argued that Fes-family PTKs may play an has been shown that the level of tyrosine phosphorylation
important role in cell physiology. Indeed, physical of inactivated Fer is increased in response to PDGF
interactions of Fes with multiple cytokine receptors and its receptor ligation (621).
ligand-induced activation through these receptors,
including those for IL-3, IL-4 and GM-CSF, has been The role of tyrosine phosphorylation sites, other
shown (611-616). Although these findings would be than Tyr-713/715, in the regulation of Fes-family PTKs is
consistent with an important role of Fes in hematopoietic unclear. At least, the negative regulation of kinase activity
cell development, mice targeted with either a kinase- of these PTKs by tyrosine phosphorylation, similar to that
inactivating mutation or a null mutation in fes developed observed in Src-family PTKs, appears unlikely. In contrast,
normally, demonstrating no significant defects (617-619), the Fes SH2 domain appears to be essential for kinase
thus arguing against the essential role of Fes in activity of Fes in vitro and in vivo (630, 635). Therefore,
hematopoiesis. However, the targeted mutation of fes, interactions of the SH2 domains of Fes-family PTKs with
resulting in production of the truncated Fes lacking both their kinase domains may stabilize the active kinase
SH2 and kinase domains, results in hyperproliferation of structure.
early myeloid cell and causes embryonic lethality
correlating with multiple developmental defects, the most Autophosphorylation of Fes occurs in trans (632)
striking being cardiovascular abnormalities, which is and, therefore, should be affected by oligomerization.
consistent with the endothelial expression of Fes (620). Indeed, both Fes and Fer are capable of forming oligomers
Furthermore, regardless of whether or not the role of Fes in through the interactions of their coiled-coil domains (621,
hematopoiesis and overall development is essential, it 622, 636, 637). The effect of these interactions on Fes and
appears to be involved in the regulation of inflammatory Fer may be different, since mutations in their coiled-coil
response (619). domains activated Fes (637), but did not affect
autophosphorylation of Fer (621). However, the importance
Ligation of PDGF receptor causes tyrosine of these interactions is supported by the finding that the
phosphorylation of Fer and its association with PDGF truncated form of Fes possessing only the FCH and coiled-
receptor in fibroblasts followed by Fer-dependent tyrosine coil (in contrast to its kinase-inactive form - see above),
phosphorylation of cortactin, which is known to inhibit the causes embryonic lethality in mice (620). It is possible that
actin crosslinking activity of this protein (621-623). this fragment of Fes disrupts oligomerization of
Furthermore, the involvement of Fer in the regulation of endogenous Fer, thus functioning as a dominant-inhibitory
adherens junctions and focal adhesions during neurite protein. It is clear, however, that the effects of coiled-coil
outgrowth (624, 625) and fibroblast adhesion (626) has domains may not be restricted to the oligomerization of
been demonstrated. These biological functions of Fer Fes-family PTK and may play other roles, such as
appear to be mediated by its effect on the N- mediating interactions of these PTKs with other coiled-coil
cadherin/catenin/Cas system. In spite of the apparent proteins.
involvement of Fer in growth-factor signaling and cell
adhesion and migration, mice expressing a targeted kinase- 3.9. Frk
inactivating mutation in fer developed normally (621, 627). The Frk family of PTKs has three members, Frk,
However, the studies with mutant mice indicate that Fer, Brk, and Srm. Frk and Brk have been cloned independently
like Fes, may be involved in the regulation of inflammatory from human, mouse and rat cells by several laboratories, and
response (627). therefore multiple names for these PTKs are used, Frk is also
known as Rak, Bsk, Iyk, and Gtk (638-642), whereas Brk is
Recent results obtained using mice carrying also known as PTK6 and Sik (643-645). Srm was cloned and
targeted inactivating mutations in both fes and fer further studied only in mice (646), but its ortholog is present in the
supported that these PTKs may play an important role in human genome, as well. Frk-family PTKs are highly
the regulation of inflammation by upregulating expression homologous to Src-family PTKs, even more so than are Csk-
of IL-10, an immunosuppressive cytokine, while not being family PTKs (1). The domain structure of Frk-family is very
essential for viability (599). These double-mutant mice also similar to that of Src-family PTKs, consisting of a highly
demonstrated defects in migration of mast cells, supporting divergent N-terminal sequence followed by an SH3 domain, an
the results obtained with fer-mutant mice (628). SH2 domain, and a tyrosine kinase domain.

Like most other PTKs, Fes-family PTKs have a Unlike Src-family PTKs, most Frk-family PTKs
conserved tyrosine in the activation loop (Tyr-713 or –715 lack the N-myristoylation site. The only exception from this
in Fes and Fer, respectively), which serves as their rule is rodent Frk, which retains the glycine residue in position
autophosphorylation site (599, 629-633). The lack of 2 and, as a consequence, is myristoylated and localized to the
autophosphorylation at Tyr-713 inhibits Fes dramatically membrane (642). Due to the lack of an N-myristoylation site,
(630). Another autophosphorylation site has been mapped Frk-family PTKs (with the exception of rodent Frk) are not
in the kinase domain of Fes (Tyr-811) (632). It is likely that targeted to the membrane. In contrast, Frk is localized to the
the N-terminal region of Fer possesses an additional nucleus (639). Recently, nuclear localization has also been
tyrosine phosphorylation site (634). Tyrosine reported for Brk (647).
phosphorylation of Fes-family PTKs is likely to be
mediated not only by their autophosphorylation, which is The divergence between the Src and Frk families
intermolecular (632), but by other PTKs as well. Thus, it of PTKs is not restricted to the lack of the N-myristoylation

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Non-receptor protein tyrosine kinases

site. The structural analysis of brk gene demonstrated that study, one may speculate that this autophosphorylation is a
its exon-intron structure is different from that of other general mechanism of activation for Frk-family PTKs.
genes encoding for non-receptor PTKs, including Src-
family PTKs (648, 649). Frk and Brk, although not Srm, possess tyrosine
residues near their C termini, which might mediate negative
Expression of Frk has been detected in the regulation of these PTKs in a Src-like fashion. Several
epithelium of small intestine, in liver, kidney, lung, skeletal studies argue in favor of this hypothesis. First, mouse Frk
muscle and, to a very low extent, in mammary epithelium with both putative negative-regulatory tyrosines mutated to
during the estrus cycle and early pregnancy, but never in phenylalanines (Y497F/Y504F) inhibits cell proliferation
brain, heart, testis or hematopoietic cells (638-642). and activates hormone production by pancreatic cells,
Epithelial expression of Frk is dramatically upregulated in whereas wild-type Frk shows no effect in these
tumors, such as hepatocellular, breast and colon carcinomas experimental systems (654, 655). Furthermore, the
(638, 641). It has also been found in B and T lymphomas in corresponding Y447F mutant of mouse Brk demonstrated
spite of its absence from normal hematopoietic cells (638). the increased kinase activity when overexpressed in
Brk has been found in skin, liver, and the intestinal tract, epithelial cells (647, 660). The activity of Y447F Brk
but not in spleen, kidney, liver, testis, lung, muscle or brain toward a peptide substrate exceeded that of
(644, 645, 650, 651). Brk is highly expressed in breast autophosphorylated wild-type Brk and was independent of
carcinomas, but not in normal breast tissue (644, 651, 652). autophosphorylation (660). These findings argue that the
It is also expressed in some melanomas (643). Therefore, negative regulation of Brk by tyrosine phosphorylation of
Frk and Brk are expressed specifically in the epithelial its C-terminal tyrosine residue is similar to that of Src-
cells, primarily those of the intestinal tract, and their family PTKs. It remains to be determined how this tyrosine
expression is dramatically upregulated in epithelial tumors. becomes phosphorylated in Brk, since it is phosphorylated
In contrast, Srm is expressed ubiquitously, although most neither by Brk itself nor by Csk, playing this role for Src-
abundantly, in lung, liver, spleen, kidney and testis (646). family PTKs (660). However, the role of the C-terminal
tyrosines in the regulation of Frk-family PTKs clearly
It has been shown that Frk binds to Rb, a cell requires further analysis, since the Y447F mutation of Brk
cycle regulator protein (653). Furthermore, a mutant of Frk has also been shown to decrease the transformation
lacking putative negative regulatory tyrosine residues potential of this PTK in fibroblasts (658).
inhibits proliferation of fibroblasts and epithelial cells (654,
655). Frk has also been shown to promote neurite 3.10. Ack
outgrowth in PC12 cells through the Crk/C3G/Rap1 Ack family of PTKs consists of two members,
pathway (656). These findings hinted that Frk might be Ack and Tnk1 (661, 662), both of which are present in
involved in the regulation of cell differentiation. However, human and mouse genomes. Two forms of Ack, Ack1 and
Frk-deficient mice demonstrated no morphological Ack2, have been described (661, 663). A catalytic kinase
abnormalities in epithelial tissues, no related metabolic or domain is positioned C-terminally in Ack PTKs and is
developmental changes, and no increase in the incidence of closely followed by an SH3 domain. In Ack, the SH3
spontaneous tumors (657). The only phenotypic change domain is immediately followed by the CRIB domain, a
detected in these mice was a slight decrease in the level of sequence capable of specific GTP-dependent binding to
circulating thyroid T3 hormone. Cdc42, but not other Rho-family GTPase (661, 663).
Homology of Tnk1 with Ack ends immediately after the
Brk has been shown to phosphorylate Sam68, SH3 domain, so Tnk1 does not possess a CRIB domain
negatively regulating its RNA-binding activity (647). Brk (662). Finally, Ack has an arrestin-like clathrin-binding
has also been shown to induce transformation of fibroblasts region, which immediately follows the CRIB domain (664).
and to sensitize mammary epithelial cells to EGF (658).
The latter is likely mediated by the functional interactions Ack isoforms are expressed highly in the brain
of Brk with ErbB3, which enhance EGF signaling via PI-3’ and skeletal muscle and, to a low extent, in lung, liver, and
kinase/Akt pathway (659). pancreas (663). Tnk1 is highly expressed in early,
immature progenitor hematopoietic cells, especially in fetal
blood, and less in other hematopoietic cells, intestine,
Functions of Srm are even less clear than those of colon, testis, ovary, fetal tissues, but not in lung, liver,
other Frk-family PTKs. Srm-deficient mice appear to be kidney or brain (662, 665).
normal, they demonstrate normal fertility and the lack of
abnormalities in the tissues expressing Srm at a high level The ability of Ack to bind to active Cdc42, a
(646). Overall, the functions of Frk-family PTKs remain to small GTPase involved in the cytoskeletal rearrangements,
be understood. implicates Ack in the cytoskeleton-mediated events.
Indeed, cell adhesion has been shown to modulate the
An analysis of mouse Brk using mutagenesis, activity of Ack. In most cases, attachment activates Ack
mass-spectrometry and enzyme kinetics indicated that Brk (663, 666, 667), but the activation in response to removal
is capable of autophosphorylation, which significantly of ECM has also been reported (668). The adhesion-
upregulates its kinase activity (660). This study mapped the induced stimulation of Ack is caused by beta-1 integrins,
autophosphorylation site of Brk to Tyr-342, a conserved but is not specific for fibronectin (666, 667). It is likely that
tyrosine residue inside the activation loop. Based on this this type of Ack stimulation is mediated by activated Cdc42

608
Non-receptor protein tyrosine kinases

(663). Furthermore, Ack is activated by stress, growth and It has been shown that Ack is activated in vivo by
nerve impulse signals (663, 669-671). The activation of activated Cdc42 (663). Although it is possible that this
Ack through EGF receptor depends on the binding of Ack activation is caused by direct binding of Ack to activated
to Grb2 and Shc, adaptor proteins known to be involved in Cdc42 (661, 663), which has been shown to induce
the growth receptor-mediated signaling (669, 672). The substantial changes in the conformation of both Cdc42 and
activation of Ack through acetylcholine receptors depends Ack (678, 679), the functional significance of the CRIB-
on the Rho-family GTPases (probably Cdc42) and Fyn mediated interactions between Ack and Cdc42 remains
(671). unclear. For example, Drosophila Ack appears to be
essential for the developmental events that are controlled
Signaling through Ack appears to regulate by Drosophila Cdc42, although this PTK possesses no
various cytoskeleton-mediated events (667, 672-674). CRIB domain and is incapable of binding to Drosophila
These effects are likely to be mediated by the Ack- Cdc42 (680).
dependent phosphorylation of Dbl, a guanine nucleotide
exchange factor (GEF) specific for Rho-family GTPases, Finally, regulation of Ack-family PTKs by SH3-
which causes activation of Dbl and, consequently, Rho- containing and/or SH3-interacting proteins similar to that
family GTPases (675). discussed for Src- and Abl-family PTKs is also possible,
because both Ack and Tnk1 possess SH3 domains and
The effect of Ack on the cytoskeleton and its proline-rich motifs. Indeed, Ack and Tnk1 have been
responsiveness to the nerve impulse argue that this PTK shown to interact with SH3 domains of multiple proteins,
may be involved in the axon guidance. This hypothesis is including Nck, Grb2 and Src (Ack) (664, 669, 672) and
supported by the recent results indicating that Drosophila PLC-gamma (Tnk1) (665). However, the role of these
Ack phosphorylates the DSH3PX1 adaptor protein inside interactions in the regulation of Ack-family PTK activity
its SH3 domain, thus turning off binding of DSH3PX1 to remains to be established.
WASP and inducing the binding of DSH3PX1 to the SH2
domain of Dock (Drosophila Nck), an adaptor protein 4. CONCLUDING REMARKS
known to be important for axon guidance (676).
However, the cytoskeleton is not the sole target of Ack, In recent years, several vertebrate and
since this PTK has been shown to activate Ras in vivo invertebrate genomes, including the human genome, have
(670), whereas its dominant-inhibitory form has been been fully sequenced, providing us with the final (or nearly
shown to block Ras-dependent cell transformation (673). final) version of the list of existing PTKs (1, 4). In light of
The effect of Ack on Ras appears to be mediated by Ack- these discoveries, it appears that the era when identification
dependent tyrosine phosphorylation and activation of Ras- of novel PTKs by cloning was a major direction of research
GRF1, a protein regulating the activity of Ras (670). in this area, is finally over. However, the genomic
Therefore, the mechanisms of the effects of Ack on the information, although important, is insufficient for
cytoskleton and cell growth are, at least to some extent, determining biological functions and regulatory
similar. mechanisms of the known PTKs, and therefore, the
research in this area is unlikely to subside any time soon.
Finally, Ack appears to bind to clathrin through
an arrestin-like clathrin-binding site (664, 677). When Ack An important finding made by the sequencing of
is overexpresed, it increases the amount of clathrin in the human and mouse genomes is that the number of non-
fraction of clathrin-coated vesicles, induces re-distribution receptor PTKs in mammals is rather small. Thirty-plus non-
of clathrin and inhibits endocytosis (664, 677). However, receptor PTKs mediate all biological functions that are
when Ack was expressed at more physiological levels, no dependent on this class of protein kinases. Moreover, only
co-localization of Ack with clathrin or clathrin re- a fraction of these PTKs are typically expressed in an
distribution was observed, making the significance of individual cell or a specific tissue. However, the number of
Ack/clathrin interactions unclear (664). molecular events in the cells and the resulting biological
responses that are dependent on non-receptor PTKs is vast.
Very little is known about the biological These phenomena are very diverse, highly specific and
functions of Tnk1, which does not posses a CRIB domain. finely regulated. How can this complexity be mediated by a
Tnk1 appears to be constitutively active, is enriched in the very limited number of non-receptor PTKs involved? It is
membrane (although is also present in the cytosol), and is likely that the answer to this question lies not in the
associated with PLC-gamma via its proline-rich region and differential specificity of non-receptor PTKs, albeit
PLC-gamma SH3 (665). considerable, but primarily in the multitude of the
interactions of non-receptor PTKs with multiple non-kinase
Little is known about the regulation of Ack- proteins that can modify the effects of these PTKs and
family PTKs. Since they are capable of regulate their functions in the cell.
autophosphorylation (663, 665, 675), their activity may be
regulated by autophosphorylation, as it has been shown for 5. ACKNOWLEDGEMENTS
other PTKs. Furthermore, Fyn appears to activate Ack in
response to acetylcholine receptor stimulation (671), thus Work in the author’s laboratory is supported by
indicating that Ack may be regulated by heterologous grants CA-78499 (National Institutes of Health) and RPG-
tyrosine phosphorylation. MBC-99450 (American Cancer Society).

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6. REFERENCES Zandieh, & X. Zhu. The sequence of the human genome.

Science 291, 1304-1351 (2001)
1. Robinson, D. R., Y. M. Wu, & S. F. Lin. The protein 3. Lander, E. S., L. M. Linton, B. Birren, C. Nusbaum, M.
tyrosine kinase family of the human genome. Oncogene 19, C. Zody, J. Baldwin, K. Devon, K. Dewar, M. Doyle, W.
5548-5557 (2000) FitzHugh, R. Funke, D. Gage, K. Harris, A. Heaford, J.
2. Venter, J. C., M. D. Adams, E. W. Myers, P. W. Li, R. Howland, L. Kann, J. Lehoczky, R. LeVine, P. McEwan,
J. Mural, G. G. Sutton, H. O. Smith, M. Yandell, C. A. K. McKernan, J. Meldrim, J. P. Mesirov, C. Miranda, W.
Evans, R. A. Holt, J. D. Gocayne, P. Amanatides, R. M. Morris, J. Naylor, C. Raymond, M. Rosetti, R. Santos, A.
Ballew, D. H. Huson, J. R. Wortman, Q. Zhang, C. D. Sheridan, C. Sougnez, N. Stange-Thomann, N. Stojanovic,
Kodira, X. H. Zheng, L. Chen, M. Skupski, G. A. Subramanian, D. Wyman, J. Rogers, J. Sulston, R.
Subramanian, P. D. Thomas, J. Zhang, G. L. Gabor Miklos, Ainscough, S. Beck, D. Bentley, J. Burton, C. Clee, N.
C. Nelson, S. Broder, A. G. Clark, J. Nadeau, V. A. Carter, A. Coulson, R. Deadman, P. Deloukas, A. Dunham,
McKusick, N. Zinder, A. J. Levine, R. J. Roberts, M. I. Dunham, R. Durbin, L. French, D. Grafham, S. Gregory,
Simon, C. Slayman, M. Hunkapiller, R. Bolanos, A. T. Hubbard, S. Humphray, A. Hunt, M. Jones, C. Lloyd, A.
Delcher, I. Dew, D. Fasulo, M. Flanigan, L. Florea, A. McMurray, L. Matthews, S. Mercer, S. Milne, J. C.
Halpern, S. Hannenhalli, S. Kravitz, S. Levy, C. Mobarry, Mullikin, A. Mungall, R. Plumb, M. Ross, R. Shownkeen,
K. Reinert, K. Remington, J. Abu-Threideh, E. Beasley, K. S. Sims, R. H. Waterston, R. K. Wilson, L. W. Hillier, J. D.
Biddick, V. Bonazzi, R. Brandon, M. Cargill, I. McPherson, M. A. Marra, E. R. Mardis, L. A. Fulton, A. T.
Chandramouliswaran, R. Charlab, K. Chaturvedi, Z. Deng, Chinwalla, K. H. Pepin, W. R. Gish, S. L. Chissoe, M. C.
V. Di Francesco, P. Dunn, K. Eilbeck, C. Evangelista, A. E. Wendl, K. D. Delehaunty, T. L. Miner, A. Delehaunty, J.
Gabrielian, W. Gan, W. Ge, F. Gong, Z. Gu, P. Guan, T. J. B. Kramer, L. L. Cook, R. S. Fulton, D. L. Johnson, P. J.
Heiman, M. E. Higgins, R. R. Ji, Z. Ke, K. A. Ketchum, Z. Minx, S. W. Clifton, T. Hawkins, E. Branscomb, P. Predki,
Lai, Y. Lei, Z. Li, J. Li, Y. Liang, X. Lin, F. Lu, G. V. P. Richardson, S. Wenning, T. Slezak, N. Doggett, J. F.
Merkulov, N. Milshina, H. M. Moore, A. K. Naik, V. A. Cheng, A. Olsen, S. Lucas, C. Elkin, E. Uberbacher, M.
Narayan, B. Neelam, D. Nusskern, D. B. Rusch, S. Frazier, R. A. Gibbs, D. M. Muzny, S. E. Scherer, J. B.
Salzberg, W. Shao, B. Shue, J. Sun, Z. Wang, A. Wang, X. Bouck, E. J. Sodergren, K. C. Worley, C. M. Rives, J. H.
Wang, J. Wang, M. Wei, R. Wides, C. Xiao, C. Yan, A. Gorrell, M. L. Metzker, S. L. Naylor, R. S. Kucherlapati,
Yao, J. Ye, M. Zhan, W. Zhang, H. Zhang, Q. Zhao, L. D. L. Nelson, G. M. Weinstock, Y. Sakaki, A. Fujiyama,
Zheng, F. Zhong, W. Zhong, S. Zhu, S. Zhao, D. Gilbert, S. M. Hattori, T. Yada, A. Toyoda, T. Itoh, C. Kawagoe, H.
Baumhueter, G. Spier, C. Carter, A. Cravchik, T. Woodage, Watanabe, Y. Totoki, T. Taylor, J. Weissenbach, R. Heilig,
F. Ali, H. An, A. Awe, D. Baldwin, H. Baden, M. W. Saurin, F. Artiguenave, P. Brottier, T. Bruls, E.
Barnstead, I. Barrow, K. Beeson, D. Busam, A. Carver, A. Pelletier, C. Robert, P. Wincker, D. R. Smith, L. Doucette-
Center, M. L. Cheng, L. Curry, S. Danaher, L. Davenport, Stamm, M. Rubenfield, K. Weinstock, H. M. Lee, J.
R. Desilets, S. Dietz, K. Dodson, L. Doup, S. Ferriera, N. Dubois, A. Rosenthal, M. Platzer, G. Nyakatura, S.
Garg, A. Gluecksmann, B. Hart, J. Haynes, C. Haynes, C. Taudien, A. Rump, H. Yang, J. Yu, J. Wang, G. Huang, J.
Heiner, S. Hladun, D. Hostin, J. Houck, T. Howland, C. Gu, L. Hood, L. Rowen, A. Madan, S. Qin, R. W. Davis, N.
Ibegwam, J. Johnson, F. Kalush, L. Kline, S. Koduru, A. A. Federspiel, A. P. Abola, M. J. Proctor, R. M. Myers, J.
Love, F. Mann, D. May, S. McCawley, T. McIntosh, I. Schmutz, M. Dickson, J. Grimwood, D. R. Cox, M. V.
McMullen, M. Moy, L. Moy, B. Murphy, K. Nelson, C. Olson, R. Kaul, N. Shimizu, K. Kawasaki, S. Minoshima,
Pfannkoch, E. Pratts, V. Puri, H. Qureshi, M. Reardon, R. G. A. Evans, M. Athanasiou, R. Schultz, B. A. Roe, F.
Rodriguez, Y. H. Rogers, D. Romblad, B. Ruhfel, R. Scott, Chen, H. Pan, J. Ramser, H. Lehrach, R. Reinhardt, W. R.
C. Sitter, M. Smallwood, E. Stewart, R. Strong, E. Suh, R. McCombie, M. de la Bastide, N. Dedhia, H. Blocker, K.
Thomas, N. N. Tint, S. Tse, C. Vech, G. Wang, J. Wetter, Hornischer, G. Nordsiek, R. Agarwala, L. Aravind, J. A.
S. Williams, M. Williams, S. Windsor, E. Winn-Deen, K. Bailey, A. Bateman, S. Batzoglou, E. Birney, P. Bork, D.
Wolfe, J. Zaveri, K. Zaveri, J. F. Abril, R. Guigo, M. J. G. Brown, C. B. Burge, L. Cerutti, H. C. Chen, D. Church,
Campbell, K. V. Sjolander, B. Karlak, A. Kejariwal, H. Mi, M. Clamp, R. R. Copley, T. Doerks, S. R. Eddy, E. E.
B. Lazareva, T. Hatton, A. Narechania, K. Diemer, A. Eichler, T. S. Furey, J. Galagan, J. G. Gilbert, C. Harmon,
Muruganujan, N. Guo, S. Sato, V. Bafna, S. Istrail, R. Y. Hayashizaki, D. Haussler, H. Hermjakob, K. Hokamp,
Lippert, R. Schwartz, B. Walenz, S. Yooseph, D. Allen, A. W. Jang, L. S. Johnson, T. A. Jones, S. Kasif, A.
Basu, J. Baxendale, L. Blick, M. Caminha, J. Carnes-Stine, Kaspryzk, S. Kennedy, W. J. Kent, P. Kitts, E. V.
P. Caulk, Y. H. Chiang, M. Coyne, C. Dahlke, A. Mays, M. Koonin, I. Korf, D. Kulp, D. Lancet, T. M. Lowe, A.
Dombroski, M. Donnelly, D. Ely, S. Esparham, C. Fosler, McLysaght, T. Mikkelsen, J. V. Moran, N. Mulder, V. J.
H. Gire, S. Glanowski, K. Glasser, A. Glodek, M. Pollara, C. P. Ponting, G. Schuler, J. Schultz, G. Slater,
Gorokhov, K. Graham, B. Gropman, M. Harris, J. Heil, S. A. F. Smit, E. Stupka, J. Szustakowski, D. Thierry-
Henderson, J. Hoover, D. Jennings, C. Jordan, J. Jordan, J. Mieg, J. Thierry-Mieg, L. Wagner, J. Wallis, R.
Kasha, L. Kagan, C. Kraft, A. Levitsky, M. Lewis, X. Liu, Wheeler, A. Williams, Y. I. Wolf, K. H. Wolfe, S. P.
J. Lopez, D. Ma, W. Majoros, J. McDaniel, S. Murphy, M. Yang, R. F. Yeh, F. Collins, M. S. Guyer, J. Peterson,
Newman, T. Nguyen, N. Nguyen, M. Nodell, S. Pan, J. A. Felsenfeld, K. A. Wetterstrand, A. Patrinos, M. J.
Peck, M. Peterson, W. Rowe, R. Sanders, J. Scott, M. Morgan, & J. Szustakowki. Initial sequencing and
Simpson, T. Smith, A. Sprague, T. Stockwell, R. Turner, E. analysis of the human genome. Nature 409, 860-921
Venter, M. Wang, M. Wen, D. Wu, M. Wu, A. Xia, A. (2001)

610
Non-receptor protein tyrosine kinases

4. Manning, G., G. Plowman, T. Hunter, & S. Sudarsanam. 23. Hubbard, S. R. Src autoinhibition: let us count the
Evolution of protein kinase signaling from yeast to man. ways. Nat Struct Biol 6, 711-714 (1999)
Trends Biochem Sci 27, 514 (2002) 24. Hubbard, S. R., & J. H. Till. Protein tyrosine kinase
5. Schlessinger, J. Cell signaling by receptor tyrosine structure and function. Annu Rev Biochem 69, 373-398
kinases. Cell 103, 211-225 (2000) (2000)
6. Leof, E. B. Growth factor receptor signalling: location, 25. Grucza, R. A., J. M. Bradshaw, K. Futterer, & G.
location, location. Trends Cell Biol 10, 343-348 (2000) Waksman. SH2 domains: from structure to energetics, a
7. Yarden, Y. The EGFR family and its ligands in human dual approach to the study of structure-function
cancer. signalling mechanisms and therapeutic relationships. Med Res Rev 19, 273-293 (1999)
opportunities. Eur J Cancer 37, S3-8. (2001) 26. Pawson, T., G. D. Gish, & P. Nash. SH2 domains,
8. Mendelsohn, J., & J. Baselga. The EGF receptor family interaction modules and cellular wiring. Trends Cell Biol
as targets for cancer therapy. Oncogene 19, 6550-6565 11, 504-511 (2001)
(2000) 27. Kay, B. K., M. P. Williamson, & M. Sudol. The
9. Patapoutian, A., & L. F. Reichardt. Trk receptors: importance of being proline: the interaction of proline-rich
mediators of neurotrophin action. Curr Opin Neurobiol 11, motifs in signaling proteins with their cognate domains.
272-280 (2001) Faseb J 14, 231-241 (2000)
10. Shibuya, M. Structure and function of VEGF/VEGF- 28. Mayer, B. J. SH3 domains: complexity in moderation.
receptor system involved in angiogenesis. Cell Struct Funct J Cell Sci 114, 1253-1263 (2001)
26, 25-35 (2001) 29. Sudol, M., H. Greulich, L. Newman, A. Sarkar, J.
11. Gschwind, A., E. Zwick, N. Prenzel, M. Leserer, & A. Sukegawa, & T. Yamamoto. A novel Yes-related kinase,
Ullrich. Cell communication networks: epidermal growth Yrk, is expressed at elevated levels in neural and
factor receptor transactivation as the paradigm for hematopoietic tissues. Oncogene 8, 823-831 (1993)
interreceptor signal transmission. Oncogene 20, 1594-1600 30. Bolen, J. B. Nonreceptor Tyrosine Protein Kinases.
(2001) Oncogene 8, 2025-2031 (1993)
12. Dickson, C., B. Spencer-Dene, C. Dillon, & V. Fantl. 31. Tsygankov, A., & J. Bolen. The Src family of tyrosine
Tyrosine kinase signalling in breast cancer: fibroblast protein kinases in hemopoietic signal transduction. Stem
growth factors and their receptors. Breast Cancer Res 2, Cells 11, 371-380 (1993)
191-196 (2000) 32. Resh, M. D. Myristylation and palmitylation of SRC
13. Zhang, X., & D. Yee. Tyrosine kinase signalling in family members - The Fats of the matter. Cell 76, 411-413
breast cancer: insulin-like growth factors and their (1994)
receptors in breast cancer. Breast Cancer Res 2, 170-175 33. Silverman, L., M. Sudol, & M. D. Resh. Members of
(2000) the src family of nonreceptor tyrosine kinases share a
14. Carraway, K. L., 3rd, & C. Sweeney. Localization and common mechanism for membrane binding. Cell Growth
modulation of ErbB receptor tyrosine kinases. Curr Opin Differ 4, 475-482 (1993)
Cell Biol 13, 125-130 (2001) 34. Ley, S. C., M. Marsh, C. R. Bebbington, K. Proudfoot,
15. Clauss, M. Molecular biology of the VEGF and the & P. Jordan. Distinct intracellular localization of Lck and
VEGF receptor family. Semin Thromb Hemost 26, 561-569 Fyn protein tyrosine kinases in human T lymphocytes. J
(2000) Cell Biol 125, 639-649 (1994)
16. Karkkainen, M. J., & T. V. Petrova. Vascular 35. Pellman, D., E. A. Garber, F. R. Cross, & H. Hanafusa.
endothelial growth factor receptors in the regulation of An N-terminal peptide from p60src can direct myristylation
angiogenesis and lymphangiogenesis. Oncogene 19, 5598- and plasma membrane localization when fused to
5605 (2000) heterologous proteins. Nature 314, 374-377 (1985)
17. Furge, K. A., Y. W. Zhang, & G. F. Vande Woude. 36. Marchildon, G. A., J. E. Casnellie, K. A. Walsh, & E.
Met receptor tyrosine kinase: enhanced signaling through G. Krebs. Covalently bound myristate in a lymphoma
adapter proteins. Oncogene 19, 5582-5589 (2000) tyrosine protein kinase. Proceedings of the National
18. Sweeney, C., & K. L. Carraway, 3rd. Ligand Academy of Sciences of the United States of America 81,
discrimination by ErbB receptors: differential signaling 7679-7682 (1984)
through differential phosphorylation site usage. Oncogene 37. Peters, D. J., B. R. McGrew, D. C. Perron, L. M.
19, 5568-5573 (2000) Liptak, & A. P. Laudano. In vivo phosphorylation and
19. McCarty, D. R., & J. Chory. Conservation and membrane association of the fyn proto-oncogene product in
innovation in plant signaling pathways. Cell 103, 201-209 IM-9 human lymphoblasts. Oncogene 5, 1313-1319 (1990)
(2000) 38. Shenoy-Scaria, A. M., L. K. Gauen, J. Kwong, A. S.
20. Hanks, S. K., & A. M. Quinn. Protein kinase catalytic Shaw, & D. M. Lublin. Palmitylation of an amino-terminal
domain sequence database: identification of conserved cysteine motif of protein tyrosine kinases p56lck and
features of primary structure and classification of family p59fyn mediates interaction with glycosyl-
members. Methods Enzymol 200, 38-62 (1991) phosphatidylinositol-anchored proteins. Molecular &
21. Williams, J. C., R. K. Wierenga, & M. Saraste. Insights Cellular Biology 13, 6385-6392 (1993)
into Src kinase functions: structural comparisons. Trends 39. Paige, L. A., M. J. S. Nadler, M. L. Harrison, J. M.
Biochem Sci 23, 179-184 (1998) Cassady, & R. L. Geahlen. Reversible palmitoylation of the
22. Hubbard, S. R. Structural analysis of receptor tyrosine protein-tyrosine kinase p56(lck). J Biol Chem 268, 8669-
kinases. Prog Biophys Mol Biol 71, 343-358 (1999) 8674 (1993)

611
Non-receptor protein tyrosine kinases

40. Koegl, M., P. Zlatkine, S. C. Ley, S. A. Courtneidge, & receptor with protein tyrosine kinase Lyn. Science 251,
A. I. Magee. Palmitoylation of multiple Src-family kinases 192-194 (1991)
at a homologous N-terminal motif. Biochem J 303, 749-753 55. Burkhardt, A. L., M. Brunswick, J. B. Bolen, & J. J.
(1994) Mond. Anti-immunoglobulin stimulation of B lymphocytes
41. Veillette, A., M. A. Bookman, E. M. Horak, & J. B. activates src-related protein-tyrosine kinases. Proceedings
Bolen. The CD4 and CD8 T cell surface antigens are of the National Academy of Sciences of the United States of
associated with the internal membrane tyrosine-protein America 88, 7410-7414 (1991)
kinase p56lck. Cell 55, 301-308 (1988) 56. Clark, M. R., K. S. Campbell, A. Kazlauskas, S. A.
42. Shaw, A. S., K. E. Amrein, C. Hammond, D. F. Stern, Johnson, M. Hertz, T. A. Potter, C. Pleiman, & J. C.
B. M. Sefton, & J. K. Rose. The lck tyrosine protein kinase Cambier. The B cell antigen receptor complex: association
interacts with the cytoplasmic tail of the CD4 glycoprotein of Ig-alpha and Ig-beta with distinct cytoplasmic effectors.
through its unique amino-terminal domain. Cell 59, 627- Science 258, 123-126 (1992)
636 (1989) 57. Lin, J., & L. B. Justement. The MB-1/B29 heterodimer
43. Burgess, K. E., A. D. Odysseos, C. Zalvan, P. couples the B cell antigen receptor to multiple src family
Anderson, S. F. Schlossman, & C. E. Rudd. Biochemical protein tyrosine kinases. Journal of Immunology 149, 1548-
identification of a direct physical interaction between the 1555 (1992)
CD4:p56lck and Ti(TcR)/CD3 complexes. Eur. J. Immunol. 58. Azzoni, L., M. Kamoun, T. W. Salcedo, P. Kanakaraj,
21, 1663-1668 (1991) & B. Perussia. Stimulation of Fc gamma RIIIA results in
44. Collins, T. L., S. Uniyal, J. Shin, J. L. Strominger, R. phospholipase C-gamma 1 tyrosine phosphorylation and
S. Mittler, & S. J. Burakoff. p56lck association with CD4 is p56lck activation. Journal of Experimental Medicine 176,
required for the interaction between CD4 and the TCR/CD3 1745-1750 (1992)
complex and for optimal antigen stimulation. J. Immunol. 59. Pignata, C., K. V. Prasad, M. J. Robertson, H. Levine,
148, 2159-2162 (1992) C. E. Rudd, & J. Ritz. Fc gamma RIIIA-mediated signaling
45. Dianzani, U., A. Shaw, B. K. al-Ramadi, R. T. Kubo, involves src-family lck in human natural killer cells.
& C. A. Janeway, Jr. Physical association of CD4 with the Journal of Immunology 151, 6794-6800 (1993)
T cell receptor. Journal of Immunology 148, 678-688 60. Hamada, F., M. Aoki, T. Akiyama, & K. Toyoshima.
(1992) Association of immunoglobulin G Fc receptor II with Src-
46. Deans, J. P., S. B. Kanner, R. M. Torres, & J. A. like protein-tyrosine kinase Fgr in neutrophils. Proceedings
Ledbetter. Interaction of CD4-lck with the T-cell of the National Academy of Sciences of the United States of
receptor/CD3 complex induces early signaling events in the America 90, 6305-6309 (1993)
absence of CD45 tyrosine phosphatase. Eur. J. Immunol. 61. Salcedo, T. W., T. Kurosaki, P. Kanakaraj, J. V.
22, 661-668 (1992) Ravetch, & B. Perussia. Physical and functional association
47. Chu, K., & D. R. Littman. Requirement for kinase of p56lck with Fc gamma RIIIA (CD16) in natural killer
activity of CD4-associated p56lck in antibody-triggered T cells. Journal of Experimental Medicine 177, 1475-1480
cell signal transduction. Journal of Biological Chemistry (1993)
269, 24095-24101 (1994) 62. Ghazizadeh, S., J. B. Bolen, & H. B. Fleit. Physical
48. Stein, P. L., H. M. Lee, S. Rich, & P. Soriano. and functional association of Src-related protein tyrosine
pp59(fyn) mutant mice display differential signaling in kinases with Fc gamma RII in monocytic THP-1 cells.
thymocytes and peripheral T-cells. Cell 70, 741-750 (1992) Journal of Biological Chemistry 269, 8878-8884 (1994)
49. Appleby, M. W., J. A. Gross, M. P. Cooke, S. D. 63. Wang, A. V., P. R. Scholl, & R. S. Geha. Physical and
Levin, X. Qian, & R. M. Perlmutter. Defective T-cell functional association of the high affinity immunoglobulin
receptor signaling in mice lacking the thymic isoform of G receptor (Fc gamma RI) with the kinases Hck and Lyn.
p59fyn. Cell 70, 751-763 (1992) Journal of Experimental Medicine 180, 1165-1170 (1994)
50. Tsygankov, A. Y., B. M. Broker, J. Fargnoli, J. A. 64. Sarmay, G., I. Pecht, & J. Gergely. Protein-tyrosine
Ledbetter, & J. B. Bolen. Activation of tyrosine kinase kinase activity tightly associated with human type II Fc
p60fyn following T-cell antigen receptor cross-linking. J. gamma receptors. Proceedings of the National Academy of
Biol. Chem. 267, 18259-18262 (1992) Sciences of the United States of America 91, 4140-4144
51. Dasilva, A. J., M. Yamamoto, C. H. Zalvan, & C. E. (1994)
Rudd. Engagement of the TcR/CD3 complex stimulates 65. Eiseman, E., & J. B. Bolen. Engagement of the high-
p59fyn(T) activity - detection of associated proteins at 72 affinity IgE receptor activates src protein-related tyrosine
kD and 120-130 kD. Mol. Immunol. 29, 1417-1425 (1992) kinases. Nature 355, 78-80 (1992)
52. Samelson, L. E., A. F. Phillips, E. T. Luong, & R. D. 66. Shakarjian, M. P., E. Eiseman, R. C. Penhallow, & J.
Klausner. Association of the fyn protein-tyrosine kinase with B. Bolen. 3-Hydroxy-3-methylglutaryl-coenzyme A
the T-cell antigen receptor. Proceedings of the National reductase inhibition in a rat mast cell line. Impairment of
Academy of Sciences of the United States of America 87, 4358- tyrosine kinase-dependent signal transduction and the
4362 (1990) subsequent degranulation response. Journal of Biological
53. Timson Gauen, L. K., A. N. Kong, L. E. Samelson, & A. Chemistry 268, 15252-15259 (1993)
S. Shaw. p59fyn tyrosine kinase associates with multiple T-cell 67. Yamashita, T., S. Y. Mao, & H. Metzger. Aggregation
receptor subunits through its unique amino-terminal domain. of the high-affinity IgE receptor and enhanced activity of
Molecular & Cellular Biology 12, 5438-5446 (1992) p53/56lyn protein-tyrosine kinase. Proceedings of the
54. Yamanashi, Y., T. Kakiuchi, J. Mizuguchi, T. National Academy of Sciences of the United States of
Yamamoto, & K. Toyoshima. Association of B cell antigen America 91, 11251-11255 (1994)

612
Non-receptor protein tyrosine kinases

68. Penhallow, R. C., K. Class, H. Sonoda, J. B. Bolen, & 81. Bewarder, N., V. Weinrich, P. Budde, D. Hartmann, H.
R. B. Rowley. Temporal activation of nontransmembrane Flaswinkel, M. Reth, & J. Frey. In vivo and in vitro
protein-tyrosine kinases following mast cell Fc epsilon RI specificity of protein tyrosine kinases for immunoglobulin
engagement. Journal of Biological Chemistry 270, 23362- G receptor (FcgammaRII) phosphorylation. Molecular &
23365 (1995) Cellular Biology 16, 4735-4743 (1996)
69. Cooke, M. P., K. M. Abraham, K. A. Forbush, & R. M. 82. Schmitz, R., G. Baumann, & H. Gram. Catalytic
Permutter. Regulation of T cell receptor signaling by a src specificity of phosphotyrosine kinases Blk, Lyn, c-Src and
family protein-tyrosine kinase (p59fyn). Cell 65, 281-291 Syk as assessed by phage display. Journal of Molecular
(1991) Biology 260, 664-677 (1996)
70. Glaichenhaus, N., N. Shastri, D. R. Littman, & J. M. 83. Rodgers, W., B. Crise, & J. K. Rose. Signals
Turner. Requirement for association of p56lck with CD4 in determining protein tyrosine kinase and glycosyl-
antigen-specific signal transduction in T cells. Cell 64, 511- phosphatidylinositol-anchored protein targeting to a
520 (1991) glycolipid-enriched membrane fraction. Mol Cell Biol 14,
71. Abraham, N., M. C. Miceli, J. R. Parnes, & A. 5384-5391 (1994)
Veillette. Enhancement of T-cell responsiveness by the 84. Arreaza, G., K. A. Melkonian, M. LaFevre-Bernt, & D.
lymphocyte-specific tyrosine protein kinase p56lck. Nature A. Brown. Triton X-100-resistant membrane complexes
350, 62-66 (1991) from cultured kidney epithelial cells contain the Src family
72. Karnitz, L., S. L. Sutor, T. Torigoe, J. C. Reed, M. P. protein tyrosine kinase p62yes. J Biol Chem 269, 19123-
Bell, D. J. Mckean, P. J. Leibson, & R. T. Abraham. 19127 (1994)
Effects of p56lck deficiency on the growth and cytolytic 85. Rodgers, W., & J. K. Rose. Exclusion of CD45 inhibits
effector function of an interleukin-2-dependent cytotoxic T- activity of p56lck associated with glycolipid-enriched
cell line. Mol Cell Biol 12, 4521-4530 (1992) membrane domains. J Cell Biol 135, 1515-1523 (1996)
73. Straus, D. B., & A. Weiss. Genetic evidence for the 86. Zlatkine, P., B. Mehul, & A. I. Magee. Retargeting of
involvement of the lck tyrosine kinase in signal cytosolic proteins to the plasma membrane by the Lck
transduction through the T cell antigen receptor. Cell 70, protein tyrosine kinase dual acylation motif. Journal of Cell
585-593 (1992) Science 110, 673-679 (1997)
74. Cone, J. C., Y. Lu, J. M. Trevillyan, J. M. Bjorndahl, & 87. Viola, A., S. Schroeder, Y. Sakakibara, & A.
C. A. Phillips. Association of the p56lck protein tyrosine Lanzavecchia. T lymphocyte costimulation mediated by
kinase with the Fc gamma RIIIA/CD16 complex in human reorganization of membrane microdomains. Science 283,
natural killer cells. European Journal of Immunology 23, 680-682 (1999)
2488-2497 (1993) 88. Zhang, W., B. J. Irvin, R. P. Trible, R. T. Abraham, &
75. Takata, M., H. Sabe, A. Hata, T. Inazu, Y. Homma, T. L. E. Samelson. Functional analysis of LAT in TCR-
Nukada, H. Yamamura, & T. Kurosaki. Tyrosine kinases mediated signaling pathways using a LAT-deficient Jurkat
Lyn and Syk regulate B cell receptor-coupled Ca2+ cell line. International Immunology 11, 943-950 (1999)
mobilization through distinct pathways. EMBO Journal 13, 89. Ilangumaran, S., S. Arni, G. van Echten-Deckert, B.
1341-1349 (1994) Borisch, & D. C. Hoessli. Microdomain-dependent
76. Tsygankov, A. Y., H. W. Kim, J. C. Pratt, C. Spana, K. regulation of Lck and Fyn protein-tyrosine kinases in T
Class, G. N. Gaulton, M. Kamoun, & J. B. Bolen. lymphocyte plasma membranes. Mol Biol Cell 10, 891-905
Diminished Tyrosine Protein Kinase Activity in T Cells (1999)
Unresponsive to TCR Stimulation. J Leukocyte Biol 55, 90. Kosugi, A., S. Saitoh, S. Noda, K. Yasuda, F. Hayashi,
289-298 (1994) M. Ogata, & T. Hamaoka. Translocation of tyrosine-
77. Beaty, C. D., T. L. Franklin, Y. Uehara, & C. B. phosphorylated TCRzeta chain to glycolipid-enriched
Wilson. Lipopolysaccharide-induced cytokine production membrane domains upon T cell activation. Int Immunol 11,
in human monocytes: role of tyrosine phosphorylation in 1395-1401 (1999)
transmembrane signal transduction. European Journal of 91. Prinetti, A., K. Iwabuchi, & S. Hakomori.
Immunology 24, 1278-1284 (1994) Glycosphingolipid-enriched signaling domain in mouse
78. Raab, M., Y. C. Cai, S. C. Bunnell, S. D. Heyeck, L. J. neuroblastoma Neuro2a cells. Mechanism of ganglioside-
Berg, & C. E. Rudd. p56Lck and p59Fyn regulate CD28 dependent neuritogenesis. J Biol Chem 274, 20916-20924
binding to phosphatidylinositol 3-kinase, growth factor (1999)
receptor-bound protein GRB-2, and T cell-specific protein- 92. Kabouridis, P. S., J. Janzen, A. L. Magee, & S. C. Ley.
tyrosine kinase ITK: implications for T-cell costimulation. Cholesterol depletion disrupts lipid rafts and modulates the
Proceedings of the National Academy of Sciences of the activity of multiple signaling pathways in T lymphocytes.
United States of America 92, 8891-8895 (1995) Eur J Immunol 30, 954-963 (2000)
79. Iwashima, M., B. A. Irving, N. S. van Oers, A. C. 93. Muller, G., C. Jung, S. Wied, S. Welte, H. Jordan, &
Chan, & A. Weiss. Sequential interactions of the TCR with W. Frick. Redistribution of glycolipid raft domain
two distinct cytoplasmic tyrosine kinases. Science 263, components induces insulin-mimetic signaling in rat
1136-1139 (1994) adipocytes. Mol Cell Biol 21, 4553-4567 (2001)
80. Flaswinkel, H., & M. Reth. Dual Role of the Tyrosine 94. Veri, M. C., K. E. DeBell, M. C. Seminario, A.
Activation Motif of the Ig-alpha Protein During Signal DiBaldassarre, I. Reischl, R. Rawat, L. Graham, C.
Transduction via the B Cell Antigen Receptor. EMBO J 13, Noviello, B. L. Rellahan, S. Miscia, R. L. Wange, & E.
83-89 (1994) Bonvini. Membrane raft-dependent regulation of

613
Non-receptor protein tyrosine kinases

phospholipase Cgamma-1 activation in T lymphocytes. Mol kinase which is separable from the epidermal growth factor
Cell Biol 21, 6939-6950 (2001) receptor. J Biol Chem 268, 26978-26982 (1993)
95. Bi, K., Y. Tanaka, N. Coudronniere, K. Sugie, S. 108. Larose, L., G. Gish, S. Shoelson, & T. Pawson.
Hong, M. J. van Stipdonk, & A. Altman. Antigen-induced Identification of residues in the beta platelet-derived
translocation of PKC-theta to membrane rafts is required growth factor receptor that confer specificity for binding to
for T cell activation. Nat Immunol 2, 556-563 (2001) phospholipase C-gamma-1. Oncogene 8, 2493-2499 (1993)
96. Gousset, K., W. F. Wolkers, N. M. Tsvetkova, A. E. 109. Mori, S., L. Ronnstrand, K. Yokote, A. Engstrom, S.
Oliver, C. L. Field, N. J. Walker, J. H. Crowe, & F. Tablin. A. Courtneidge, L. Claesson-Welsh, & C. H. Heldin.
Evidence for a physiological role for membrane rafts in Identification of two juxtamembrane autophosphorylation
human platelets. J Cell Physiol 190, 117-128 (2002) sites in the PDGF beta-receptor, involvement in the
97. Horak, I. D., R. E. Gress, P. J. Lucas, E. M. Horak, T. interaction with Src family tyrosine kinases. EMBO
A. Waldmann, & J. B. Bolen. T-lymphocyte interleukin 2- Journal 12, 2257-2264 (1993)
dependent tyrosine protein kinase signal tranduction 110. Twamley-Stein, G. M., R. Pepperkok, W. Ansorge, &
involves the activation of p56lck. Proc. Natl. Acad. Sci. USA S. A. Courtneidge. The Src family tyrosine kinases are
88, 1996-2000 (1991) required for platelet-derived growth factor-mediated signal
98. Torigoe, T., R. O-Connor, R. Fagard, S. Fischer, D. transduction in NIH 3T3 cells. Proceedings of the National
Santoli, & J. C. Reed. Regulation of SRC-family protein Academy of Sciences of the United States of America 90,
tyrosine kinases by interleukins, IL-2, and IL-3. Leukemia 7696-7700 (1993)
6, 94S-97S (1992) 111. Landgren, E., P. Blume-Jensen, S. A. Courtneidge, &
99. Kobayashi, N., T. Kono, M. Hatakeyama, Y. Minami, L. Claesson-Welsh. Fibroblast growth factor receptor-1
T. Miyazaki, R. M. Perlmutter, & T. Taniguchi. Functional regulation of Src family kinases. Oncogene 10, 2027-2035
coupling of the src-family protein tyrosine kinases p59fyn (1995)
and p53/56lyn with the interleukin 2 receptor: Implications 112. Fuhrer, D. K., & Y. C. Yang. Complex formation of
for redundancy and pleiotropism in cytokine signal JAK2 with PP2A, P13K, and Yes in response to the
transduction. Proc. Natl. Acad. Sci. USA 90, 4201-4205 hematopoietic cytokine interleukin-11. Biochemical &
(1993) Biophysical Research Communications 224, 289-296
100. Taichman, R., I. Merida, T. Torigoe, G. N. Gaulton, (1996)
& J. C. Reed. Evidence That Protein Tyrosine Kinase p56- 113. Uddin, S., D. A. Sher, Y. Alsayed, S. Pons, O. R.
Lck Regulates the Activity of Phosphatidylinositol-3'- Colamonici, E. N. Fish, M. F. White, & L. C. Platanias.
kinase in Interleukin-2-Dependent T-Cells. J Biol Chem Interaction of p59fyn with interferon-activated Jak kinases.
268, 20031-20036 (1993) Biochemical & Biophysical Research Communications 235,
101. Shibuya, H., K. Kohu, K. Yamada, E. L. Barsoumian, 83-88 (1997)
R. M. Perlmutter, & T. Taniguchi. Functional dissection of 114. Sayeski, P. P., M. S. Ali, K. Hawks, S. J. Frank, & K.
p56(lck), a protein tyrosine kinase which mediates E. Bernstein. The angiotensin II-dependent association of
interleukin-2-induced activation of the c-fos gene. Mol Cell Jak2 and c-Src requires the N-terminus of Jak2 and the SH2
Biol 14, 5812-5819 (1994) domain of c-Src. Circ Res 84, 1332-1338 (1999)
102. Miyazaki, T., Z. J. Liu, A. Kawahara, Y. Minami, K. 115. Clark, E. A., & J. S. Brugge. Redistribution of
Yamada, Y. Tsujimoto, E. L. Barsoumian, R. M. Permutter, activated pp60c-src to integrin-dependent cytoskeletal
& T. Taniguchi. Three distinct IL-2 signaling pathways complexes in thrombin-stimulated platelets. Mol Cell Biol
mediated by bcl-2, c-myc, and lck cooperate in 13, 1863-1871 (1993)
hematopoietic cell proliferation. Cell 81, 223-231 (1995) 116. Hamaguchi, M., H. Xiao, Y. Uehara, Y. Ohnishi, &
103. Anderson, S. M., & B. Jorgensen. Activation of src- Y. Nagai. Herbimycin-A inhibits the association of p60(v-
related tyrosine kinases by IL-3. Journal of Immunology src) with the cytoskeletal structure and with
155, 1660-1670 (1995) phosphatidylinositol-3' kinase. Oncogene 8, 559-564
104. Hallek, M., C. Neumann, M. Schaffer, S. Danhauser- (1993)
Riedl, N. von Bubnoff, G. de Vos, B. J. Druker, K. 117. Fox, J. E. B., L. Lipfert, E. A. Clark, C. C. Reynolds,
Yasukawa, J. D. Griffin, & B. Emmerich. Signal C. D. Austin, & J. S. Brugge. On the role of the platelet
transduction of interleukin-6 involves tyrosine membrane skeleton in mediating signal transduction -
phosphorylation of multiple cytosolic proteins and Association of GP-IIb-IIIa, pp60(c-src), pp62(c-yes), and
activation of Src-family kinases Fyn, Hck, and Lyn in the p21(ras) GTPase-activating protein with the membrane
multiple myeloma cell lines. Exp Hematol 25, 1367-1377 skeleton. J Biol Chem 268, 25973-25984 (1993)
(1997) 118. Weng, Z., J. A. Taylor, C. E. Turner, J. S. Brugge, & C.
105. Chaturvedi, P., M. V. Reddy, & E. P. Reddy. Src Seidel-Dugan. Detection of Src homology 3-binding proteins,
kinases and not JAKs activate STATs during IL-3 induced including paxillin, in normal and v-Src-transformed Balb/c
myeloid cell proliferation. Oncogene 16, 1749-1758 (1998) 3T3 cells. Journal of Biological Chemistry 268, 14956-14963
106. Courtneidge, S. A., R. Dhand, D. Pilat, G. M. (1993)
Twamley, M. D. Waterfield, & M. F. Roussel. Activation 119. Minoguchi, K., H. Kihara, H. Nishikata, M. M. Hamawy,
of Src family kinases by colony stimulating factor-1, and & R. P. Siraganian. Src family tyrosine kinase Lyn binds
their association with its receptor. EMBO J 12, 943-950 several proteins including paxillin in rat basophilic leukemia
(1993) cells. Molecular Immunology 31, 519-529 (1994)
107. Filhol, O., E. M. Chambaz, G. N. Gill, & C. Cochet. 120. Schaller, M. D., J. D. Hildebrand, J. D. Shannon, J.
Epidermal growth factor stimulates a protein tyrosine W. Fox, R. R. Vines, & J. T. Parsons. Autophosphorylation

614
Non-receptor protein tyrosine kinases

of the focal adhesion kinase, pp125FAK, directs SH2- 136. Soriano, P., C. Montgomery, R. Geske, & A. Bradley.
dependent binding of pp60src. Molecular & Cellular Targeted disruption of the c-src proto-oncogene leads to
Biology 14, 1680-1688 (1994) osteopetrosis in mice. Cell 64, 693-702 (1991)
121. Xing, Z., H. C. Chen, J. K. Nowlen, S. J. Taylor, D. 137. Boyce, B. F., T. Yoneda, C. Lowe, P. Soriano, & G.
Shalloway, & J. L. Guan. Direct interaction of v-Src with R. Mundy. Requirement of pp60c-src expression for
the focal adhesion kinase mediated by the Src SH2 domain. osteoclasts to form ruffled borders and resorb bone in mice.
Molecular Biology of the Cell 5, 413-421 (1994) J Clin Invest 90, 1622-1627. (1992)
122. Kaplan, K. B., K. B. Bibbins, J. R. Swedlow, M. 138. Molina, T. J., K. Kishihara, D. P. Siderovski, W. Van
Arnaud, D. O. Morgan, & H. E. Varmus. Association of the Ewijk, A. Narendran, E. Timms, A. Wakeham, C. J. Paige,
amino-terminal half of c-Src with focal adhesions alters K.-U. Hartmann, A. Veillette, D. Davidson, & T. W. Mak.
their properties and is regulated by phosphorylation of Profound block in thymocyte development in mice lacking
tyrosine 527. EMBO J 13, 4745-4756 (1994) p56LCK. Nature 357, 161-164 (1992)
123. Thomas, S. M., P. Soriano, & A. Imamoto. Specific 139. Molina, T. J., M. F. Bachmann, T. M. Kundig, R. M.
and redundant roles of Src and Fyn in organizing the Zinkernagel, & T. W. Mak. Peripheral T-cells in mice
cytoskeleton. Nature 376, 267-271 (1995) lacking p56(lck) do not express significant antiviral
124. Cobb, B. S., M. D. Schaller, T. H. Leu, & J. T. effector functions. J Immunol 151, 699-706 (1993)
Parsons. Stable association of pp60src and pp59fyn with 140. Wen, T., L. Zhang, S. K. Kung, T. J. Molina, R. G.
the focal adhesion-associated protein tyrosine kinase, Miller, & T. W. Mak. Allo-skin graft rejection, tumor
pp125FAK. Molecular & Cellular Biology 14, 147-155 rejection and natural killer activity in mice lacking p56lck.
(1994) European Journal of Immunology 25, 3155-3159 (1995)
125. Eide, B. L., C. W. Turck, & J. A. Escobedo. 141. Anderson, S. J., S. D. Levin, & R. M. Perlmutter.
Identification of Tyr-397 as the primary site of tyrosine Protein tyrosine kinase p56(lck) controls allelic exclusion
phosphorylation and pp60src association in the focal of T-cell receptor beta-chain genes. Nature 365, 552-554
adhesion kinase, pp125FAK. Molecular & Cellular Biology (1993)
15, 2819-2827 (1995) 142. Mombaerts, P., S. J. Anderson, R. M. Perlmutter, T.
126. Dikic, I., G. Tokiwa, S. Lev, S. A. Courtneidge, & J. W. Mak, & S. Tonegawa. An activated lck transgene
Schlessinger. A role for Pyk2 and Src in linking G-protein- promotes thymocyte development in RAG-1 mutant mice.
coupled receptors with MAP kinase activation. Nature 383, Immunity 1, 261-267 (1994)
547-550 (1996) 143. Grant, S. G., T. J. O'Dell, K. A. Karl, P. L. Stein, P.
127. Ma, Y. C., J. Huang, S. Ali, W. Lowry, & X. Y. Soriano, & E. R. Kandel. Impaired long-term potentiation,
Huang. Src tyrosine kinase is a novel direct effector of G spatial learning, and hippocampal development in fyn
proteins. Cell 102, 635-646 (2000) mutant mice. Science 258, 1903-1910. (1992)
128. Wang, J. Y. J. Nuclear protein tyrosine kinases. 144. Umemori, H., S. Sato, T. Yagi, S. Aizawa, & T.
Trends Biochem Sci 19, 373-376 (1994) Yamamoto. Initial events of myelination involve Fyn
129. Zhao, Y., M. Sudol, H. Hanafusa, & J. Krueger. tyrosine kinase signalling. Nature 367, 572-576 (1994)
Increased tyrosine kinase activity of c-Src during calcium- 145. Miyakawa, T., T. Yagi, S. Watanabe, & H. Niki.
induced keratinocyte differentiation. Proceedings of the Increased fearfulness of Fyn tyrosine kinase deficient mice.
National Academy of Sciences of the United States of Mol Brain Res 27, 179-182 (1994)
America 89, 8298-8302 (1992) 146. Beggs, H. E., P. Soriano, & P. F. Maness. NCAM-
130. Bagrodia, S., I. Chackalaparampil, T. E. Kmiecik, dependent neurite outgrowth is inhibited in neurons from
& D. Shalloway. Altered tyrosine 527 phosphorylation Fyn-minus mice. J Cell Biol 127, 825-833 (1994)
and mitotic activation of p60c-src. Nature 349, 172-175 147. Calautti, E., C. Missero, P. L. Stein, R. M. Ezzell, &
(1991) G. P. Dotto. Fyn tyrosine kinase is involved in keratinocyte
131. Kaech, S., B. Schnierle, A. Wyss, & K. differentiation control. Genes & Development 9, 2279-2291
Ballmerhofer. Myristylation and amino-terminal (1995)
phosphorylation are required for activation of pp60(c- 148. Hibbs, M. L., D. M. Tarlinton, J. Armes, D. Grail, G.
src) during mitosis. Oncogene 8, 575-581 (1993) Hodgson, R. Maglitto, S. A. Stacker, & A. R. Dunn.
132. Bagrodia, S., S. J. Taylor, & D. Shalloway. Multiple defects in the immune system of Lyn-deficient
Myristylation is required for Tyr-527 dephosphorylation mice, culminating in autoimmune disease. Cell 83, 301-311
and activation of pp60c-src in mitosis. Molecular & (1995)
Cellular Biology 13, 1464-1470 (1993) 149. Nishizumi, H., I. Taniuchi, Y. Yamanashi, D. Kitamura,
133. Bagrodia, S., A. P. Laudano, & D. Shalloway. D. Ilic, S. Mori, T. Watanabe, & T. Yamamoto. Impaired
Accessibility of the C-SRC Sh2-domain for binding is proliferation of peripheral B cells and indication of
increased during mitosis. J Biol Chem 269, 10247- autoimmune disease in lyn-deficient mice. Immunity 3, 549-
10251 (1994) 560 (1995)
134. Fumagalli, S., N. F. Totty, J. J. Hsuan, & S. A. 150. Lowell, C. A., & P. Soriano. Knockouts of Src-family
Courtneidge. A target for SRC in mitosis. Nature 368, kinases: stiff bones, wimpy T cells, and bad memories. Genes
871-874 (1994) & Development 10, 1845-1857 (1996)
135. Park, J., & C. A. Cartwright. Src activity increases 151. Lowell, C. A., M. Niwa, P. Soriano, & H. E. Varmus.
and Yes activity decreases during mitosis of human Deficiency of the Hck and Src tyrosine kinases results in
colon carcinoma cells. Molecular & Cellular Biology extreme levels of extramedullary hematopoiesis. Blood 87,
15, 2374-2382 (1995) 1780-1792 (1996)

615
Non-receptor protein tyrosine kinases

152. Vanoers, N. S. C., B. Lowinkropf, D. Finlay, K. 166. Xu, W., A. Doshi, M. Lei, M. J. Eck, & S. C.
Connolly, & A. Weiss. Alpha-beta T cell development is Harrison. Crystal structures of c-Src reveal features of its
abolished in mice lacking both Lck and Fyn protein autoinhibitory mechanism. Mol Cell 3, 629-638 (1999)
pyrosine kinases. Immunity 5, 429-436 (1996) 167. Schindler, T., F. Sicheri, A. Pico, A. Gazit, A.
153. Lowell, C. A., P. Soriano, & H. E. Varmus. Levitzki, & J. Kuriyan. Crystal structure of Hck in complex
Functional overlap in the Src gene family - inactivation of with a Src family-selective tyrosine kinase inhibitor. Mol
Hck and Fgr impairs natural immunity. Gene Develop 8, Cell 3, 639-648 (1999)
387-398 (1994) 168. Roussel, R. R., S. R. Brodeur, D. Shalloway, & A. P.
154. Lowell, C. A., L. Fumagalli, & G. Berton. Deficiency Laudano. Selective binding of activated pp60c-src by an
of Src family kinases p59/61hck and p58c-fgr results in immobilized synthetic phosphopeptide modeled on the
defective adhesion-dependent neutrophil functions. J Cell carboxyl terminus of pp60c-src. Proceedings of the
Biol 133, 895-910 (1996) National Academy of Sciences of the United States of
155. Meng, F., & C. A. Lowell. A beta 1 integrin signaling America 88, 10696-10700 (1991)
pathway involving Src-family kinases, Cbl and PI-3 kinase 169. Liu, X., S. R. Brodeur, G. Gish, Z. Songyang, L. C.
is required for macrophage spreading and migration. Cantley, A. P. Laudano, & T. Pawson. Regulation of c-Src
EMBO Journal 17, 4391-4403 (1998) tyrosine kinase activity by the Src SH2 domain. Oncogene
156. Cooper, J. A., & A. MacAuley. Potential positive and 8, 1119-1126 (1993)
negative autoregulation of p60c-src by intermolecular 170. Amrein, K. E., B. Panholzer, N. A. Flint, W.
autophosphorylation. Proc Natl Acad Sci U S A 85, 4232- Bannwarth, & P. Burn. The Src homology 2 domain of the
4236 (1988) protein-tyrosine kinase p56lck mediates both
157. Barker, S. C., D. B. Kassel, D. Weigl, X. Huang, M. intermolecular and intramolecular interactions.
A. Luther, & W. B. Knight. Characterization of pp60c-src Proceedings of the National Academy of Sciences of the
tyrosine kinase activities using a continuous assay: United States of America 90, 10285-10289 (1993)
autoactivation of the enzyme is an intermolecular 171. Weijland, A., J. C. Williams, G. Neubauer, S. A.
autophosphorylation process. Biochemistry 34, 14843- Courtneidge, R. K. Wierenga, & G. Superti-Furga. Src
14851 (1995) regulated by C-terminal phosphorylation is monomeric.
158. Sotirellis, N., T. M. Johnson, M. L. Hibbs, I. J. Proceedings of the National Academy of Sciences of the
Stanley, E. Stanley, A. R. Dunn, & H. C. Cheng. United States of America 94, 3590-3595 (1997)
Autophosphorylation induces autoactivation and a decrease 172. Gonfloni, S., F. Frischknecht, M. Way, & G. Superti-
in the Src homology 2 domain accessibility of the Lyn Furga. Leucine 255 of Src couples intramolecular
protein kinase. Journal of Biological Chemistry 270, interactions to inhibition of catalysis. Nat Struct Biol 6,
29773-29780 (1995) 760-764 (1999)
159. Zhou, S., K. L. Carraway, M. J. Eck, S. C. Harrison, 173. Cartwright, C. A., W. Eckhart, S. Simon, & P. L.
R. A. Feldman, M. Mohammadi, J. Schlessinger, S. R. Kaplan. Cell transformation by pp60c-src mutated in the
Hubbard, D. P. Smith, C. Eng, M. J. Lorenzo, B. A. J. carboxy-terminal regulatory domain. Cell 49, 83-91 (1987)
Ponder, B. J. Mayer, & L. C. Cantley. Catalytic specificity 174. Reynolds, A. B., J. Vila, T. J. Lansing, W. M. Potts,
of protein-tyrosine kinases is critical for selective M. J. Weber, & J. T. Parsons. Activation of the oncogenic
signalling. Nature 373, 536-539 (1995) potential of the avian cellular src protein by specific
160. Hardwick, J. S., & B. M. Sefton. Activation of the structural alteration of the carboxy terminus. EMBO
Lck tyrosine protein kinase by hydrogen peroxide requires Journal 6, 2359-2364 (1987)
the phosphorylation of Tyr-394. Proceedings of the 175. Marth, J. D., J. A. Cooper, C. S. King, S. F. Ziegler,
National Academy of Sciences of the United States of D. A. Tinker, R. W. Overell, E. G. Krebs, & R. M.
America 92, 4527-4531 (1995) Perlmutter. Neoplastic transformation induced by an
161. Chiang, G. G., & B. M. Sefton. Phosphorylation of a activated lymphocyte-specific protein tyrosine kinase
Src kinase at the autophosphorylation site in the absence of (pp56lck). Molecular & Cellular Biology 8, 540-550
Src kinase activity. J Biol Chem 275, 6055-6058 (2000) (1988)
162. Yamaguchi, H., & W. A. Hendrickson. Structural 176. Kawakami, T., Y. Kawakami, S. A. Aaronson, & K.
basis for activation of human lymphocyte kinase Lck C. Robbins. Acquisition of transforming properties by
upon tyrosine phosphorylation. Nature 384, 484-489 FYN, a normal SRC-related human gene. Proceedings of
(1996) the National Academy of Sciences of the United States of
163. Xu, W., S. C. Harrison, & M. J. Eck. Three- America 85, 3870-3874 (1988)
dimensional structure of the tyrosine kinase c-Src. Nature 177. Hirai, H., & H. E. Varmus. Mutations in src
385, 595-602 (1997) homology regions 2 and 3 of activated chicken c-src that
164. Williams, J. C., A. Weijland, S. Gonfloni, A. result in preferential transformation of mouse or chicken
Thompson, S. A. Courtneidge, G. Superti-Furga, & R. K. cells. Proceedings of the National Academy of Sciences of
Wierenga. The 2.35 A crystal structure of the inactivated the United States of America 87, 8592-8596 (1990)
form of chicken Src: a dynamic molecule with multiple 178. Reynolds, P. J., T. R. Hurley, & B. M. Sefton.
regulatory interactions. J Mol Biol 274, 757-775 (1997) Functional analysis of the SH2 and SH3 domains of the lck
165. Sicheri, F., I. Moarefi, & J. Kuriyan. Crystal tyrosine protein kinase. Oncogene 7, 1949-1955 (1992)
structure of the Src family tyrosine kinase Hck. Nature 179. Veillette, A., L. Caron, M. Fournel, & T. Pawson.
385, 602-609 (1997) Regulation of the enzymatic function of the lymphocyte-

616
Non-receptor protein tyrosine kinases

specific tyrosine protein kinase p56lck by the non-catalytic lck, fyn, and c-src tyrosine protein kinases. Molecular &
SH2 and SH3 domains. Oncogene 7, 971-980 (1992) Cellular Biology 13, 1651-1656 (1993)
180. Seideldugan, C., B. E. Meyer, S. M. Thomas, & J. S. 194. Sieh, M., J. B. Bolen, & A. Weiss. CD45 specifically
Brugge. Effects of SH2 and SH3 deletions on the functional modulates binding of Lck to a phosphopeptide
activities of wild-type and transforming variants of c-Src. encompassing the negative regulatory tyrosine of Lck.
Mol Cell Biol 12, 1835-1845 (1992) EMBO Journal 12, 315-321 (1993)
181. Thomas, J. E., P. Soriano, & J. S. Brugge. 195. Biffen, M., D. Mcmichaelphillips, T. Larson, A.
Phosphorylation of c-Src on tyrosine 527 by another Venkitaraman, & D. Alexander. The CD45 tyrosine
protein tyrosine kinase. Science 254, 568-571 (1991) phosphatase regulates specific pools of antigen receptor-
182. Okada, M., S. Nada, Y. Yamanashi, T. Yamamoto, & associated p59(Fyn) and CD4-associated p56(Lck) tyrosine
H. Nakagawa. CSK: a protein-tyrosine kinase involved in kinases in human T-cells. EMBO J 13, 1920-1929 (1994)
regulation of src family kinases. Journal of Biological 196. Zheng, X. M., Y. Wang, & C. J. Pallen. Cell
Chemistry 266, 24249-24252 (1991) transformation and activation of pp60c-src by
183. Bergman, M., T. Mustelin, C. Oetken, J. Partanen, N. overexpression of a protein tyrosine phosphatase. Nature
A. Flint, K. E. Amrein, M. Autero, P. Burn, & K. Alitalo. 359, 336-339 (1992)
The human p50csk tyrosine kinase phosphorylates p56lck 197. Fang, K. S., H. Sabe, H. Saito, & H. Hanafusa.
at Tyr-505 and down regulates its catalytic activity. EMBO Comparative study of three protein-tyrosine phosphatases.
J 11, 2919-2924 (1992) Chicken protein-tyrosine phosphatase lambda
184. Sabe, H., M. Okada, H. Nakagawa, & H. Hanafusa. dephosphorylates c-Src tyrosine 527. Journal of Biological
Activation of c-Src in cells bearing v-Crk and its Chemistry 269, 20194-20200 (1994)
suppression by Csk. Molecular & Cellular Biology 12, 198. Harder, K. W., N. P. Moller, J. W. Peacock, & F. R.
4706-4713 (1992) Jirik. Protein-tyrosine phosphatase alpha regulates Src
185. Nada, S., T. Yagi, H. Takeda, T. Tokunaga, H. family kinases and alters cell-substratum adhesion. J Biol
Nakagawa, Y. Ikawa, M. Okada, & S. Aizawa. Constitutive Chem 273, 31890-31900 (1998)
activation of Src family kinases in mouse embryos that lack 199. Pani, G., K. D. Fischer, I. Mlinaricrascan, & K. A.
Csk. Cell 73, 1125-1135 (1993) Siminovitch. Signaling capacity of the T cell antigen
186. Takeuchi, M., S. Kuramochi, N. Fusaki, S. Nada, J. receptor is negatively regulated by the PTP1C tyrosine
Kawamura-Tsuzuku, S. Matsuda, K. Semba, K. phosphatase. Journal of Experimental Medicine 184, 839-
Toyoshima, M. Okada, & T. Yamamoto. Functional and 852 (1996)
physical interaction of protein-tyrosine kinases Fyn and 200. Raab, M., & C. E. Rudd. Hematopoietic cell
Csk in the T-cell signaling system. Journal of Biological phosphatase (HCP) regulates p56LCK phosphorylation and
Chemistry 268, 27413-27419 (1993) ZAP-70 binding to T cell receptor zeta chain. Biochem
187. Chow, L. M., M. Fournel, D. Davidson, & A. Biophys Res Commun 222, 50-57 (1996)
Veillette. Negative regulation of T-cell receptor signalling 201. Plas, D. R., R. Johnson, J. T. Pingel, R. J. Matthews,
by tyrosine protein kinase p50csk. Nature 365, 156-160 M. Dalton, G. Roy, A. C. Chan, & M. L. Thomas. Direct
(1993) regulation of ZAP-70 by SHP-1 in T cell antigen receptor
188. Superti-Furga, G., S. Fumagalli, M. Koegl, S. A. signaling. Science 272, 1173-1176 (1996)
Courtneidge, & G. Draetta. Csk inhibition of c-Src activity 202. Cloutier, J. F., & A. Veillette. Cooperative inhibition
requires both the SH2 and SH3 domains of Src. EMBO of T-cell antigen receptor signaling by a complex between
Journal 12, 2625-2634 (1993) a kinase and a phosphatase. Journal of Experimental
189. Mustelin, T., K. M. Coggeshall, & A. Altman. Rapid Medicine 189, 111-121 (1999)
activation of the T-cell tyrosine protein kinase pp56lck by 203. Alonso, G., M. Koegl, N. Mazurenko, & S. A.
the CD45 phosphotyrosine phosphatase. Proceedings of the Courtneidge. Sequence requirements for binding of Src family
National Academy of Sciences of the United States of tyrosine kinases to activated growth factor receptors. Journal
America 86, 6302-6306 (1989) of Biological Chemistry 270, 9840-9848 (1995)
190. Mustelin, T., & A. Altman. Dephosphorylation and 204. Burnham, M. R., P. J. Bruce-Staskal, M. T. Harte, C. L.
activation of the T cell tyrosine kinase pp56lck by the Weidow, A. Ma, S. A. Weed, & A. H. Bouton. Regulation of
leukocyte common antigen (CD45). Oncogene 5, 809-813 c-SRC activity and function by the adapter protein CAS. Mol
(1990) Cell Biol 20, 5865-5878 (2000)
191. Mustelin, T., T. Pessa-Morikawa, M. Autero, M. 205. Alexandropoulos, K., & D. Baltimore. Coordinate
Gassmann, L. C. Andersson, C. G. Gahmberg, & P. Burn. activation of c-Src by SH3- and SH2-binding sites on a novel
Regulation of the p59fyn protein tyrosine kinase by the p130Cas-related protein, Sin. Genes Dev 10, 1341-1355 (1996)
CD45 phosphotyrosine phosphatase. European Journal of 206. Moarefi, I., M. LaFevre-Bernt, F. Sicheri, M. Huse, C. H.
Immunology 22, 1173-1178 (1992) Lee, J. Kuriyan, & W. T. Miller. Activation of the Src-family
192. Shiroo, M., L. Goff, M. Biffen, E. Shivnan, & D. tyrosine kinase Hck by SH3 domain displacement. Nature 385,
Alexander. CD45 tyrosine phosphatase-activated p59fyn 650-653 (1997)
couples the T cell antigen receptor to pathways of 207. Briggs, S. D., M. Sharkey, M. Stevenson, & T. E.
diacylglycerol production, protein kinase C activation and Smithgall. SH3-mediated Hck tyrosine kinase activation and
calcium influx. EMBO Journal 11, 4887-4897 (1992) fibroblast transformation by the Nef protein of HIV-1. J Biol
193. Hurley, T. R., R. Hyman, & B. M. Sefton. Chem 272, 17899-17902 (1997)
Differential effects of expression of the CD45 tyrosine 208. Veillette, A., I. D. Horak, E. M. Horak, M. A.
protein phosphatase on the tyrosine phosphorylation of the Bookman, & J. B. Bolen. Alterations of the lymphocyte-

617
Non-receptor protein tyrosine kinases

specific protein tyrosine kinase (p56lck) during T-cell 223. Bjorge, J. D., A. Jakymiw, & D. J. Fujita. Selected
activation. Molecular & Cellular Biology 8, 4353-4361 glimpses into the activation and function of src kinase.
(1988) Oncogene 19, 5620-5635 (2000)
209. Veillette, A., I. D. Horak, & J. B. Bolen. Post- 224. Lamers, M. B., A. A. Antson, R. E. Hubbard, R. K.
translational alterations of the tyrosine kinase p56lck in Scott, & D. H. Williams. Structure of the protein tyrosine
response to activators of protein kinase C. Oncogene kinase domain of C-terminal Src kinase (CSK) in complex
Research 2, 385-401 (1988) with staurosporine. J Mol Biol 285, 713-725 (1999)
210. Luo, K. X., & B. M. Sefton. Analysis of the sites in 225. Okada, M., & H. Nakagawa. A protein tyrosine
p56lck whose phosphorylation is induced by tetradecanoyl kinase involved in regulation of pp60c-src function. J Biol
phorbol acetate. Oncogene 5, 803-808 (1990) Chem 264, 20886-20893 (1989)
211. Winkler, D. G., I. Park, T. Kim, N. S. Payne, C. T. 226. Nada, S., M. Okada, A. MacAuley, J. A. Cooper, &
Walsh, J. L. Strominger, & J. Shin. Phosphorylation of Ser- H. Nakagawa. Cloning of a complementary DNA for a
42 and Ser-59 in the N-terminal region of the tyrosine protein-tyrosine kinase that specifically phosphorylates a
kinase p56(lck). Proc Natl Acad Sci USA 90, 5176-5180 negative regulatiry site of p60c-src. Nature 351, 69-72
(1993) (1991)
212. Watts, J. D., J. S. Sanghera, S. L. Pelech, & R. 227. Chow, L. M. L., C. Jarvis, Q. L. Hu, S. H. Nye, F. G.
Aebersold. Phosphorylation of Serine-59 of p56(lck) in Gervais, A. Veillette, & L. A. Matis. Ntk: A Csk-related
activated T-cells. J Biol Chem 268, 23275-23282 (1993) protein-tyrosine kinase expressed in brain and T
213. Watts, J. D., M. J. Welham, L. Kalt, J. W. Schrader, lymphocytes. Proc Natl Acad Sci USA 91, 4975-4979
& R. Aebersold. IL-2 stimulation of T-lymphocytes (1994)
induces sequential activation of mitogen-activated protein 228. McVicar, D. W., B. K. Lal, A. Lloyd, M. Kawamura,
kinases and phosphorylation of p56(lck) at Serine-59. J Y. Q. Chen, X. Y. Zhang, J. E. Staples, J. R. Ortaldo, & J.
Immunol 151, 6862-6871 (1993) J. Oshea. Molecular cloning of lsk, a carboxyl-terminal src
214. Schmitt, J. M., & P. J. Stork. PKA phosphorylation of kinase (csk) related gene, expressed in leukocytes.
Src mediates cAMP's inhibition of cell growth via Rap1. Oncogene 9, 2037-2044 (1994)
Mol Cell 9, 85-94 (2002) 229. Bennett, B. D., S. Cowley, S. X. Jiang, R. London, B.
215. Couture, C., G. Baier, C. Oetken, S. Williams, D. J. Deng, J. Grabarek, J. E. Groopman, D. V. Goeddel, & H.
Telford, A. Marie-Cardine, G. Baier-Bitterlich, S. Fischer, Avraham. Identification and Characterization of a Novel
P. Burn, A. Altman, & T. Mustelin. Activation of p56lck by Tyrosine Kinase from Megakaryocytes. J Biol Chem 269,
p72syk through physical association and N-terminal 1068-1074 (1994)
tyrosine phosphorylation. Molecular & Cellular Biology 230. Sondhi, D., W. Xu, Z. Songyang, M. J. Eck, & P. A.
14, 5249-5258 (1994) Cole. Peptide and protein phosphorylation by protein
216. Couture, C., Z. Songyang, T. Jascur, S. Williams, P. tyrosine kinase Csk: insights into specificity and
Tailor, L. C. Cantley, & T. Mustelin. Regulation of the Lck mechanism. Biochemistry 37, 165-172 (1998)
SH2 domain by tyrosine phosphorylation. Journal of 231. Autero, M., J. Saharinen, T. Pessa-Morikawa, M.
Biological Chemistry 271, 24880-24884 (1996) Soula-Rothhut, C. Oetken, M. Gassmann, M. Bergman, K.
217. Stover, D. R., P. Furet, & N. B. Lydon. Modulation of Alitalo, P. Burn, C. G. Gahmberg, & T. Mustelin. Tyrosine
the SH2 binding specificity and kinase activity of Src by phosphorylation of CD45 phosphotyrosine phosphatase by
tyrosine phosphorylation within its SH2 domain. J Biol p50csk kinase creates a binding site for p56lck tyrosine
Chem 271, 12481-12487 (1996) kinase and activates the phosphatase. Molecular & Cellular
218. Broome, M. A., & T. Hunter. The PDGF receptor Biology 14, 1308-1321 (1994)
phosphorylates Tyr 138 in the c-Src SH3 domain in vivo 232. Imamoto, A., & P. Soriano. Disruption of the csk
reducing peptide ligand binding. Oncogene 14, 17-34 gene, encoding a negative regulator of Src family tyrosine
(1997) kinases, leads to neural tube defects and embryonic
219. Harris, K. F., I. Shoji, E. M. Cooper, S. Kumar, H. lethality in mice. Cell 73, 1117-1124 (1993)
Oda, & P. M. Howley. Ubiquitin-mediated degradation of 233. Gross, J., M. Appleby, S. Chien, S. Nada, S.
active Src tyrosine kinase. Proc Natl Acad Sci U S A 96, Bartelmez, M. Okada, S. Aizawa, & R. Perlmutter. Control
13738-13743 (1999) of lymphopoiesis by p50csk, a regulatory protein tyrosine
220. Hakak, Y., & G. S. Martin. Ubiquitin-dependent kinase. J. Exp. Med. 181, 463-473 (1995)
degradation of active Src. Curr Biol 9, 1039-1042 234. Hamaguchi, I., N. Yamaguchi, J. Suda, A. Iwama, A.
(1999) Hirao, M. Hashiyama, S. Aizawa, & T. Suda. Analysis of
221. Andoniou, C. E., N. L. Lill, C. B. Thien, M. L. CSK homologous kinase (CHK/HYL) in hematopoiesis by
Lupher, Jr., S. Ota, D. D. Bowtell, R. M. Scaife, W. Y. utilizing gene knockout mice. Biochemical & Biophysical
Langdon, & H. Band. The Cbl proto-oncogene product Research Communications 224, 172-179 (1996)
negatively regulates the Src-family tyrosine kinase Fyn 235. Davidson, D., L. M. Chow, & A. Veillette. Chk, a
by enhancing its degradation. Molecular & Cellular Csk family tyrosine protein kinase, exhibits Csk-like
Biology 20, 851-867 (2000) activity in fibroblasts, but not in an antigen-specific T-cell
222. Yokouchi, M., T. Kondo, A. Sanjay, A. Houghton, line. J Biol Chem 272, 1355-1362 (1997)
A. Yoshimura, S. Komiya, H. Zhang, & R. Baron. Src- 236. Yamashita, H., S. Avraham, S. Jiang, I. Dikic, & H.
catalyzed phosphorylation of c-Cbl leads to the Avraham. The Csk homologous kinase associates with
interdependent ubiquitination of both proteins. J Biol TrkA receptors and is involved in neurite outgrowth of
Chem 276, 35185-35193 (2001) PC12 cells. J Biol Chem 274, 15059-15065 (1999)

618
Non-receptor protein tyrosine kinases

237. Vang, T., K. M. Torgersen, V. Sundvold, M. Saxena, antigen receptor zeta and CD3 epsilon from activated
F. O. Levy, B. S. Skalhegg, V. Hansson, T. Mustelin, & K. Jurkat T cells. J Biol Chem 268, 19797-19801 (1993)
Tasken. Activation of the COOH-terminal Src kinase (Csk) 252. Bu, J. Y., A. S. Shaw, & A. C. Chan. Analysis of the
by cAMP-dependent protein kinase inhibits signaling interaction of ZAP-70 and syk protein-tyrosine kinases
through the T cell receptor. J Exp Med 193, 497-507 (2001) with the T-cell antigen receptor by plasmon resonance.
238. Maca, R. D. The effects of cyclic nucleotides on the Proceedings of the National Academy of Sciences of the
proliferation of cultured human T-lymphocytes. United States of America 92, 5106-5110 (1995)
Immunopharmacology 8, 53-60 (1984) 253. Isakov, N., R. L. Wange, W. H. Burgess, J. D. Watts,
239. Muraguchi, A., K. Miyazaki, J. H. Kehrl, & A. S. R. Aebersold, & L. E. Samelson. ZAP-70 binding
Fauci. Inhibition of human B cell activation by diterpine specificity to T cell receptor tyrosine-based activation
forskolin: interference with B cell growth factor-induced motifs: the tandem SH2 domains of ZAP-70 bind distinct
G1 to S transition of the B cell cycle. J Immunol 133, 1283- tyrosine-based activation motifs with varying affinity.
1287 (1984) Journal of Experimental Medicine 181, 375-380 (1995)
240. Blomhoff, H. K., E. B. Smeland, K. Beiske, R. 254. Chan, A. C., B. A. Irving, J. D. Fraser, & A. Weiss.
Blomhoff, E. Ruud, T. Bjoro, S. Pfeifer-Ohlsson, R. Watt, The zeta chain is associated with a tyrosine kinase and
S. Funderud, T. Godal, & R. Ohlsson. Cyclic AMP- upon T-cell antigen receptor stimulation associates with
mediated suppression of normal and neoplastic B cell ZAP-70, a 70-kDa tyrosine phosphoprotein. Proceedings of
proliferation is associated with regulation of myc and Ha- the National Academy of Sciences of the United States of
ras protooncogenes. J Cell Physiol 131, 426-433 (1987) America 88, 9166-9170 (1991)
241. Takayama, H., G. Trenn, & M. V. Sitkovsky. Locus 255. Wange, R. L., A. N. Kong, & L. E. Samelson. A
of inhibitory action of cAMP-dependent protein kinase in tyrosine-phosphorylated 70-kDa protein binds a
the antigen receptor-triggered cytotoxic T lymphocyte photoaffinity analogue of ATP and associates with both the
activation pathway. J Biol Chem 263, 2330-2336 (1988) zeta chain and CD3 components of the activated T cell
242. Holte, H., P. Torjesen, H. K. Blomhoff, E. Ruud, S. antigen receptor. Journal of Biological Chemistry 267,
Funderud, & E. B. Smeland. Cyclic AMP has the ability to 11685-11688 (1992)
influence multiple events during B cell stimulation. Eur J 256. Chan, A. C., M. Iwashima, C. W. Turck, & A. Weiss.
Immunol 18, 1359-1366 (1988) ZAP-70: a 70 kd protein-tyrosine kinase that associates
243. Johnson, K. W., B. H. Davis, & K. A. Smith. cAMP with the TCR zeta chain. Cell 71, 649-662 (1992)
antagonizes interleukin 2-promoted T-cell cycle 257. Yamada, T., T. Taniguchi, C. Yang, S. Yasue, H.
progression at a discrete point in early G1. Proc Natl Acad Saito, & H. Yamamura. Association of B-cell-antigen
Sci U S A 85, 6072-6076 (1988) receptor with protein-tyrosine kinase-p72(syk) and
244. Gray, L. S., J. Gnarra, E. L. Hewlett, & V. H. activation by engagement of membrane IgM. Eur J
Engelhard. Increased intracellular cyclic adenosine Biochem 213, 455-459 (1993)
monophosphate inhibits T lymphocyte-mediated cytolysis 258. Benhamou, M., N. J. Ryba, H. Kihara, H. Nishikata,
by two distinct mechanisms. J Exp Med 167, 1963-1968 & R. P. Siraganian. Protein-tyrosine kinase p72syk in high
(1988) affinity IgE receptor signaling. Identification as a
245. Sondhi, D., & P. A. Cole. Domain interactions in component of pp72 and association with the receptor
protein tyrosine kinase Csk. Biochemistry 38, 11147-11155 gamma chain after receptor aggregation. Journal of
(1999) Biological Chemistry 268, 23318-23324 (1993)
246. Kawabuchi, M., Y. Satomi, T. Takao, Y. Shimonishi, S. 259. Kurosaki, T., S. A. Johnson, L. Pao, K. Sada, H.
Nada, K. Nagai, A. Tarakhovsky, & M. Okada. Yamamura, & J. C. Cambier. Role of the Syk
Transmembrane phosphoprotein Cbp regulates the activities of autophosphorylation site and SH2 domains in B cell
Src-family tyrosine kinases. Nature 404, 999-1003 (2000) antigen receptor signaling. Journal of Experimental
247. Brdicka, T., D. Pavlistova, A. Leo, E. Bruyns, V. Medicine 182, 1815-1823 (1995)
Korinek, P. Angelisova, J. Scherer, A. Shevchenko, I. Hilgert, 260. Qian, D., M. N. Mollenauer, & A. Weiss. Dominant-
J. Cerny, K. Drbal, Y. Kuramitsu, B. Kornacker, V. Horejsi, & negative zeta-associated protein 70 inhibits T cell antigen
B. Schraven. Phosphoprotein associated with receptor signaling. Journal of Experimental Medicine 183,
glycosphingolipid-enriched microdomains (PAG), a novel 611-620 (1996)
ubiquitously expressed transmembrane adaptor protein, binds 261. Northrop, J. P., M. J. Pustelnik, A. T. Lu, & J. R.
the protein tyrosine kinase csk and is involved in regulation of Grove. Characterization of the roles of SH2 domain-
T cell activation. J Exp Med 191, 1591-1604 (2000) containing proteins in T-lymphocyte activation by using
248. Latour, S., & A. Veillette. Proximal protein tyrosine dominant negative SH2 domains. Molecular & Cellular
kinases in immunoreceptor signaling. Curr Opin Immunol 13, Biology 16, 2255-2263 (1996)
299-306 (2001) 262. Jouvin, M. H., M. Adamczewski, R. Numerof, O.
249. Sada, K., T. Takano, S. Yanagi, & H. Yamamura. Letourneur, A. Valle, & J. P. Kinet. Differential control of
Structure and function of syk protein-tyrosine kinase. J the tyrosine kinases Lyn and Syk by the two signaling
Biochem (Tokyo) 130, 177-186 (2001) chains of the high affinity immunoglobulin E receptor.
250. Yanagi, S., R. Inatome, T. Takano, & H. Yamamura. Syk Journal of Biological Chemistry 269, 5918-5925 (1994)
expression and novel function in a wide variety of tissues. 263. Chan, A. C., N. S. van Oers, A. Tran, L. Turka, C. L.
Biochem Biophys Res Commun 288, 495-498 (2001) Law, J. C. Ryan, E. A. Clark, & A. Weiss. Differential
251. Wange, R. L., S. N. Malek, S. Desiderio, & L. E. expression of ZAP-70 and Syk protein tyrosine kinases,
Samelson. Tandem SH2 domains of ZAP-70 bind to T cell and the role of this family of protein tyrosine kinases in

619
Non-receptor protein tyrosine kinases

TCR signaling. Journal of Immunology 152, 4758-4766 277. Wange, R. L., R. Guitian, N. Isakov, J. D. Watts, R.
(1994) Aebersold, & L. E. Samelson. Activating and inhibitory
264. Nagai, K., M. Takata, H. Yamamura, & T. Kurosaki. mutations in adjacent tyrosines in the kinase domain of
Tyrosine phosphorylation of Shc is mediated through Lyn ZAP-70. Journal of Biological Chemistry 270, 18730-
and Syk in B cell receptor signaling. Journal of Biological 18733 (1995)
Chemistry 270, 6824-6829 (1995) 278. Chan, A. C., M. Dalton, R. Johnson, G. H. Kong, T.
265. Jabril-Cuenod, B., C. Zhang, A. M. Scharenberg, R. Wang, R. Thoma, & T. Kurosaki. Activation of ZAP-70
Paolini, R. Numerof, M. A. Beaven, & J. P. Kinet. Syk- kinase activity by phosphorylation of tyrosine 493 is
dependent phosphorylation of Shc. A potential link required for lymphocyte antigen receptor function. EMBO
between FcepsilonRI and the Ras/mitogen-activated protein Journal 14, 2499-2508 (1995)
kinase signaling pathway through SOS and Grb2. Journal 279. Weil, R., J. F. Cloutier, M. Fournel, & A. Veillette.
of Biological Chemistry 271, 16268-16272 (1996) Regulation of Zap-70 by Src family tyrosine protein
266. Deckert, M., S. Tartare-Deckert, C. Couture, T. kinases in an antigen-specific T-cell line. Journal of
Mustelin, & A. Altman. Functional and physical Biological Chemistry 270, 2791-2799 (1995)
interactions of Syk family kinases with the Vav proto- 280. van Oers, N. S., N. Killeen, & A. Weiss. Lck
oncogene product. Immunity 5, 591-604 (1996) regulates the tyrosine phosphorylation of the T cell receptor
267. Law, C. L., K. A. Chandran, S. P. Sidorenko, & E. A. subunits and ZAP-70 in murine thymocytes. Journal of
Clark. Phospholipase C-gamma1 interacts with conserved Experimental Medicine 183, 1053-1062 (1996)
phosphotyrosyl residues in the linker region of Syk and is a 281. Kolanus, W., C. Romeo, & B. Seed. T cell activation
substrate for Syk. Molecular & Cellular Biology 16, 1305- by clustered tyrosine kinases. Cell 74, 171-183 (1993)
1315 (1996) 282. Couture, C., G. Baier, A. Altman, & T. Mustelin.
268. Raab, M., A. J. da Silva, P. R. Findell, & C. E. Rudd. p56(lck)-independent activation and tyrosine
Regulation of Vav-SLP-76 binding by ZAP-70 and its phosphorylation of p72(syk) by T-cell antigen
relevance to TCR zeta/CD3 induction of interleukin-2. receptor/CD3 stimulation. Proc Natl Acad Sci USA 91,
Immunity 6, 155-164 (1997) 5301-5305 (1994)
269. Hendricks-Taylor, L. R., D. G. Motto, J. Zhang, R. P. 283. Chu, D. H., H. Spits, J. F. Peyron, R. B. Rowley, J. B.
Siraganian, & G. A. Koretzky. SLP-76 is a substrate of the Bolen, & A. Weiss. The Syk protein tyrosine kinase can
high affinity IgE receptor-stimulated protein tyrosine function independently of CD45 or Lck in T cell antigen
kinases in rat basophilic leukemia cells. Journal of receptor signaling. EMBO Journal 15, 6251-6261 (1996)
Biological Chemistry 272, 1363-1367 (1997) 284. Zoller, K. E., I. A. Macneil, & J. S. Brugge. Protein
270. Beitz, L. O., D. A. Fruman, T. Kurosaki, L. C. tyrosine kinases Syk and Zap-70 display distinct
Cantley, & A. M. Scharenberg. SYK is upstream of requirements for Src family kinases in immune response
phosphoinositide 3-kinase in B cell receptor signaling. receptor signal transduction. Journal of Immunology 158,
Journal of Biological Chemistry 274, 32662-32666 (1999) 1650-1659 (1997)
271. Gross, B. S., J. R. Lee, J. L. Clements, M. Turner, V. 285. Latour, S., L. M. L. Chow, & A. Veillette.
L. Tybulewicz, P. R. Findell, G. A. Koretzky, & S. P. Differential intrinsic enzymatic activity of Syk and Zap-70
Watson. Tyrosine phosphorylation of SLP-76 is protein-tyrosine kinases. Journal of Biological Chemistry
downstream of Syk following stimulation of the collagen 271, 22782-22790 (1996)
receptor in platelets. J Biol Chem 274, 5963-5971 (1999) 286. Shiue, L., M. J. Zoller, & J. S. Brugge. Syk is
272. Gross, B. S., S. K. Melford, & S. P. Watson. activated by phosphotyrosine-containing peptides
Evidence that phospholipase C-gamma2 interacts with representing the tyrosine-based activation motifs of the
SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain high affinity receptor for IgE. Journal of Biological
after stimulation of the collagen receptor glycoprotein VI in Chemistry 270, 10498-10502 (1995)
human platelets. Eur J Biochem 263, 612-623 (1999) 287. Rowley, R. B., A. L. Burkhardt, H. G. Chao, G. R.
273. Shan, X., & R. L. Wange. Itk/Emt/Tsk activation in Matsueda, & J. B. Bolen. Syk protein-tyrosine kinase is
response to CD3 cross-linking in Jurkat T cells requires regulated by tyrosine-phosphorylated Ig alpha/Ig beta
ZAP-70 and Lat and is independent of membrane immunoreceptor tyrosine activation motif binding and
recruitment. J Biol Chem 274, 29323-29330 (1999) autophosphorylation. Journal of Biological Chemistry 270,
274. Ching, K. A., J. A. Grasis, P. Tailor, Y. Kawakami, T. 11590-11594 (1995)
Kawakami, & C. D. Tsoukas. TCR/CD3-Induced activation 288. Kimura, T., H. Sakamoto, E. Appella, & R. P.
and binding of Emt/Itk to linker of activated T cell Siraganian. Conformational changes induced in the protein
complexes: requirement for the Src homology 2 domain. J tyrosine kinase p72syk by tyrosine phosphorylation or by
Immunol 165, 256-262 (2000) binding of phosphorylated immunoreceptor tyrosine-based
275. Baba, Y., S. Hashimoto, M. Matsushita, D. Watanabe, activation motif peptides. Molecular & Cellular Biology
T. Kishimoto, T. Kurosaki, & S. Tsukada. BLNK mediates 16, 1471-1478 (1996)
Syk-dependent Btk activation. Proc Natl Acad Sci U S A 289. Isakov, N., R. L. Wange, J. D. Watts, R. Aebersold, &
98, 2582-2586 (2001) L. E. Samelson. Purification and characterization of human
276. Kurosaki, T., M. Takata, Y. Yamanashi, T. Inazu, T. ZAP-70 protein-tyrosine kinase from a baculovirus
Taniguchi, T. Yamamoto, & H. Yamamura. Syk activation expression system. Journal of Biological Chemistry 271,
by the Src-family tyrosine kinase in the B cell receptor 15753-15761 (1996)
signaling. Journal of Experimental Medicine 179, 1725- 290. Futterer, K., J. Wong, R. A. Grucza, A. C. Chan, & G.
1729 (1994) Waksman. Structural basis for Syk tyrosine kinase ubiquity

620
Non-receptor protein tyrosine kinases

in signal transduction pathways revealed by the crystal 303. Turner, M., E. Schweighoffer, F. Colucci, J. P. Di
structure of its regulatory SH2 domains bound to a dually Santo, & V. L. Tybulewicz. Tyrosine kinase SYK: essential
phosphorylated ITAM peptide. J Mol Biol 281, 523-537 functions for immunoreceptor signalling. Immunol Today
(1998) 21, 148-154 (2000)
291. Rowley, R. B., J. B. Bolen, & J. Fargnoli. Molecular 304. Chu, D. H., N. S. van Oers, M. Malissen, J. Harris, M.
cloning of rodent p72Syk. Evidence of alternative mRNA Elder, & A. Weiss. Pre-T cell receptor signals are
splicing. Journal of Biological Chemistry 270, 12659- responsible for the down-regulation of Syk protein tyrosine
12664 (1995) kinase expression. J Immunol 163, 2610-2620 (1999)
292. Latour, S., J. Zhang, R. P. Siraganian, & A. Veillette. 305. Watts, J. D., M. Affolter, D. L. Krebs, R. L. Wange,
A unique insert in the linker domain of Syk is necessary for L. E. Samelson, & R. Aebersold. Identification by
its function in immunoreceptor signalling. Embo J 17, electrospray ionization mass spectrometry of the sites of
2584-2595 (1998) tyrosine phosphorylation induced in activated Jurkat T cells
293. Williams, S., C. Couture, J. Gilman, T. Jascur, M. on the protein tyrosine kinase ZAP-70. Journal of
Deckert, A. Altman, & T. Mustelin. Reconstitution of T Biological Chemistry 269, 29520-29529 (1994)
cell antigen receptor-induced Erk2 kinase activation in 306. Di Bartolo, V., D. Mege, V. Germain, M. Pelosi, E.
Lck-negative JCaM1 cells by Syk. European Journal of Dufour, F. Michel, G. Magistrelli, A. Isacchi, & O. Acuto.
Biochemistry 245, 84-90 (1997) Tyrosine 319, a newly identified phosphorylation site of
294. Williams, B. L., K. L. Schreiber, W. Zhang, R. L. ZAP-70, plays a critical role in T cell antigen receptor
Wange, L. E. Samelson, P. J. Leibson, & R. T. Abraham. signaling. Journal of Biological Chemistry 274, 6285-6294
Genetic evidence for differential coupling of Syk family (1999)
kinases to the T-cell receptor: reconstitution studies in a 307. Furlong, M. T., A. M. Mahrenholz, K. H. Kim, C. L.
ZAP-70-deficient Jurkat T-cell line. Mol Cell Biol 18, Ashendel, M. L. Harrison, & R. L. Geahlen. Identification
1388-1399 (1998) of the major sites of autophosphorylation of the murine
295. Stewart, Z. A., & J. A. Pietenpol. Syk: a new player protein-tyrosine kinase Syk. Biochimica et Biophysica Acta
in the field of breast cancer. Breast Cancer Res 3, 5-7 - Molecular Cell Research 1355, 177-190 (1997)
(2001) 308. Keshvara, L. M., C. C. Isaacson, T. M. Yankee, R.
296. Negishi, I., N. Motoyama, K. Nakayama, K. Sarac, M. L. Harrison, & R. L. Geahlen. Syk- and Lyn-
Nakayama, S. Senju, S. Hatakeyama, Q. Zhang, A. C. dependent phosphorylation of Syk on multiple tyrosines
Chan, & D. Y. Loh. Essential role for ZAP-70 in both following B cell activation includes a site that negatively
positive and negative selection of thymocytes. Nature 376, regulates signaling. J Immunol 161, 5276-5283 (1998)
435-438 (1995) 309. Magistrelli, G., R. Bosotti, B. Valsasina, C. Visco, R.
297. Wiest, D. L., J. M. Ashe, T. K. Howcroft, H. M. Lee, Perego, S. Toma, O. Acuto, & A. Isacchi. Role of the Src
D. M. Kemper, I. Negishi, D. S. Singer, A. Singer, & R. homology 2 domains and interdomain regions in ZAP-70
Abe. A spontaneously arising mutation in the DLAARN phosphorylation and enzymatic activity. Eur J Biochem
motif of murine ZAP-70 abrogates kinase activity and 266, 1166-1173 (1999)
arrests thymocyte development. Immunity 6, 663-671 310. Zhao, Q., B. L. Williams, R. T. Abraham, & A.
(1997) Weiss. Interdomain B in ZAP-70 regulates but is not
298. Turner, M., P. J. Mee, P. S. Costello, O. Williams, A. required for ZAP-70 signaling function in lymphocytes.
A. Price, L. P. Duddy, M. T. Furlong, R. L. Geahlen, & V. Mol Cell Biol 19, 948-956 (1999)
L. Tybulewicz. Perinatal lethality and blocked B-cell 311. Zhao, Q., & A. Weiss. Enhancement of lymphocyte
development in mice lacking the tyrosine kinase Syk. responsiveness by a gain-of-function mutation of ZAP-70.
Nature 378, 298-302 (1995) Molecular & Cellular Biology 16, 6765-6774 (1996)
299. Cheng, A. M., B. Rowley, W. Pao, A. Hayday, J. B. 312. Kong, G., M. Dalton, J. B. Wardenburg, D. Straus, T.
Bolen, & T. Pawson. Syk tyrosine kinase required for Kurosaki, & A. C. Chan. Distinct tyrosine phosphorylation
mouse viability and B-cell development. Nature 378, 303- sites in ZAP-70 mediate activation and negative regulation
306 (1995) of antigen receptor function. Mol Cell Biol 16, 5026-5035
300. Turner, M., A. Gulbranson-Judge, M. E. Quinn, A. E. (1996)
Walters, I. C. MacLennan, & V. L. Tybulewicz. Syk 313. Yankee, T. M., L. M. Keshvara, S. Sawasdikosol, M.
tyrosine kinase is required for the positive selection of L. Harrison, & R. L. Geahlen. Inhibition of signaling
immature B cells into the recirculating B cell pool. J Exp through the B cell antigen receptor by the protooncogene
Med 186, 2013-2021 (1997) product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl
301. Law, C. L., S. P. Sidorenko, K. A. Chandran, K. E. phosphotyrosine-binding domain. Journal of Immunology
Draves, A. C. Chan, A. Weiss, S. Edelhoff, C. M. Disteche, 163, 5827-5835 (1999)
& E. A. Clark. Molecular cloning of human Syk. A B cell 314. Sada, K., J. Zhang, & R. P. Siraganian. Point
protein-tyrosine kinase associated with the surface mutation of a tyrosine in the linker region of Syk results in
immunoglobulin M-B cell receptor complex. Journal of a gain of function. Journal of Immunology 164, 338-344
Biological Chemistry 269, 12310-12319 (1994) (2000)
302. Gong, Q., L. White, R. Johnson, M. White, I. Negishi, 315. Lupher, M. L., Jr., Z. Songyang, S. E. Shoelson, L. C.
M. Thomas, & A. C. Chan. Restoration of thymocyte Cantley, & H. Band. The Cbl phosphotyrosine-binding
development and function in zap-70-/- mice by the Syk domain selects a D(N/D)XpY motif and binds to the
protein tyrosine kinase. Immunity 7, 369-377 (1997) Tyr292 negative regulatory phosphorylation site of ZAP-

621
Non-receptor protein tyrosine kinases

70. Journal of Biological Chemistry 272, 33140-33144 329. Tamagnone, L., I. Lahtinen, T. Mustonen, K.
(1997) Virtaneva, F. Francis, F. Muscatelli, R. Alitalo, C. I. Smith,
316. Lupher, M. L., Jr., N. Rao, N. L. Lill, C. E. Andoniou, C. Larsson, & K. Alitalo. BMX, a novel nonreceptor
S. Miyake, E. A. Clark, B. Druker, & H. Band. Cbl- tyrosine kinase gene of the BTK/ITK/TEC/TXK family
mediated negative regulation of the Syk tyrosine kinase. A located in chromosome Xp22.2. Oncogene 9, 3683-3688
critical role for Cbl phosphotyrosine-binding domain (1994)
binding to Syk phosphotyrosine 323. Journal of Biological 330. Smith, C. I., T. C. Islam, P. T. Mattsson, A. J.
Chemistry 273, 35273-35281 (1998) Mohamed, B. F. Nore, & M. Vihinen. The Tec family of
317. Rao, N., M. L. Lupher, S. Ota, K. A. Reedquist, B. J. cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk,
Druker, & H. Band. The linker phosphorylation site Tyr292 Tec, Txk and homologs in other species. Bioessays 23, 436-
mediates the negative regulatory effect of Cbl on ZAP-70 446 (2001)
in T cells. J Immunol 164, 4616-4626 (2000) 331. Haire, R. N., Y. Ohta, J. E. Lewis, S. M. Fu, P.
318. Pelosi, M., V. Di Bartolo, V. Mounier, D. Mege, J. M. Kroisel, & G. W. Litman. TXK, a novel human tyrosine
Pascussi, E. Dufour, A. Blondel, & O. Acuto. Tyrosine 319 kinase expressed in T cells shares sequence identity with
in the interdomain B of ZAP-70 is a binding site for the Src Tec family kinases and maps to 4p12. Hum Mol Genet 3,
homology 2 domain of Lck. J Biol Chem 274, 14229-14237 897-901 (1994)
(1999) 332. Sommers, C. L., K. Huang, E. W. Shores, A.
319. Williams, B. L., B. J. Irvin, S. L. Sutor, C. C. Chini, Grinberg, D. A. Charlick, C. A. Kozak, & P. E. Love.
E. Yacyshyn, J. Bubeck Wardenburg, M. Dalton, A. C. Murine txk: a protein tyrosine kinase gene regulated by T
Chan, & R. T. Abraham. Phosphorylation of Tyr319 in cell activation. Oncogene 11, 245-251 (1995)
ZAP-70 is required for T-cell antigen receptor-dependent 333. Hu, Q., D. Davidson, P. L. Schwartzberg, F.
phospholipase C-gamma1 and Ras activation. EMBO Macchiarini, M. J. Lenardo, J. A. Bluestone, & L. A. Matis.
Journal 18, 1832-1844 (1999) Identification of Rlk, a novel protein tyrosine kinase with
320. Wu, J., Q. Zhao, T. Kurosaki, & A. Weiss. The Vav predominant expression in the T cell lineage. Journal of
binding site (Y315) in ZAP-70 is critical for antigen Biological Chemistry 270, 1928-1934 (1995)
receptor-mediated signal transduction. Journal of 334. Ohta, Y., R. N. Haire, C. T. Amemiya, R. T. Litman,
Experimental Medicine 185, 1877-1882 (1997) T. Trager, O. Riess, & G. W. Litman. Human Txk:
321. Michel, F., L. Grimaud, L. Tuosto, & O. Acuto. Fyn genomic organization, structure and contiguous physical
and ZAP-70 are required for Vav phosphorylation in T linkage with the Tec gene. Oncogene 12, 937-942 (1996)
cells stimulated by antigen-presenting cells. J Biol Chem 335. Debnath, J., M. Chamorro, M. J. Czar, E. M. Schaeffer,
273, 31932-31938 (1998) M. J. Lenardo, H. E. Varmus, & P. L. Schwartzberg. Rlk/TXk
322. Couture, C., S. Williams, N. Gauthier, P. Tailor, & T. encodes two forms of a novel cysteine string tyrosine kinase
Mustelin. Role of Tyr518 and Tyr519 in the regulation of activated by Src family kinases. Molecular & Cellular Biology
catalytic activity and substrate phosphorylation by Syk 19, 1498-1507 (1999)
protein-tyrosine kinase. European Journal of Biochemistry 336. Qiu, Y., & H. J. Kung. Signaling network of the btk
246, 447-451 (1997) family kinases. Oncogene 19, 5651-5661 (2000)
323. Zhang, J., T. Kimura, & R. P. Siraganian. Mutations 337. Fukuda, M., T. Kojima, H. Kabayama, & K. Mikoshiba.
in the activation loop tyrosines of protein tyrosine kinase Mutation of the pleckstrin homology domain of Bruton's
Syk abrogate intracellular signaling but not kinase activity. tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-
J Immunol 161, 4366-4374 (1998) tetrakisphosphate binding capacity. J Biol Chem 271, 30303-
324. Couture, C., M. Deckert, S. Williams, F. O. Russo, A. 30306 (1996)
Altman, & T. Mustelin. Identification of the site in the Syk 338. Salim, K., M. J. Bottomley, E. Querfurth, M. J. Zvelebil,
protein tyrosine kinase that binds the SH2 domain of Lck. I. Gout, R. Scaife, R. L. Margolis, R. Gigg, C. I. Smith, P. C.
Journal of Biological Chemistry 271, 24294-24299 (1996) Driscoll, M. D. Waterfield, & G. Panayotou. Distinct
325. Zeitlmann, L., T. Knorr, M. Knoll, C. Romeo, P. specificity in the recognition of phosphoinositides by the
Sirim, & W. Kolanus. T cell activation induced by novel pleckstrin homology domains of dynamin and Bruton's
gain-of-function mutants of Syk and ZAP-70. J Biol Chem tyrosine kinase. Embo J 15, 6241-6250 (1996)
273, 15445-15452 (1998) 339. Rameh, L. E., A. Arvidsson, K. L. Carraway, 3rd, A. D.
326. Visco, C., G. Magistrelli, R. Bosotti, R. Perego, L. Couvillon, G. Rathbun, A. Crompton, B. VanRenterghem, M.
Rusconi, S. Toma, M. Zamai, O. Acuto, & A. Isacchi. P. Czech, K. S. Ravichandran, S. J. Burakoff, D. S. Wang, C.
Activation of Zap-70 tyrosine kinase due to a structural S. Chen, & L. C. Cantley. A comparative analysis of the
rearrangement induced by tyrosine phosphorylation and/or phosphoinositide binding specificity of pleckstrin homology
ITAM binding. Biochemistry 39, 2784-2791 (2000) domains. J Biol Chem 272, 22059-22066 (1997)
327. Ota, S., K. Hazeki, N. Rao, M. L. Lupher, Jr., C. E. 340. Kojima, T., M. Fukuda, Y. Watanabe, F. Hamazato, &
Andoniou, B. Druker, & H. Band. The RING finger domain of K. Mikoshiba. Characterization of the pleckstrin homology
Cbl is essential for negative regulation of the Syk tyrosine domain of Btk as an inositol polyphosphate and
kinase. Journal of Biological Chemistry 275, 414-422 (2000) phosphoinositide binding domain. Biochem Biophys Res
328. Rao, N., A. K. Ghosh, S. Ota, P. Zhou, A. L. Reddi, Commun 236, 333-339 (1997)
K. Hakezi, B. K. Druker, J. Wu, & H. Band. The non- 341. Kavran, J. M., D. E. Klein, A. Lee, M. Falasca, S. J.
receptor tyrosine kinase Syk is a target of Cbl-mediated Isakoff, E. Y. Skolnik, & M. A. Lemmon. Specificity and
ubiquitylation upon B-cell receptor stimulation. Embo J 20, promiscuity in phosphoinositide binding by pleckstrin
7085-7095 (2001) homology domains. J Biol Chem 273, 30497-30508 (1998)

622
Non-receptor protein tyrosine kinases

342. Satterthwaite, A. B., F. Willis, P. Kanchanastit, D. 354. Hashimoto, S., A. Iwamatsu, M. Ishiai, K. Okawa, T.
Fruman, L. C. Cantley, C. D. Helgason, R. K. Humphries, Yamadori, M. Matsushita, Y. Baba, T. Kishimoto, T.
C. A. Lowell, M. Simon, M. Leitges, A. Tarakhovsky, T. F. Kurosaki, & S. Tsukada. Identification of the SH2 domain
Tedder, R. Lesche, H. Wu, & O. N. Witte. A sensitized binding protein of Bruton's tyrosine kinase as BLNK--
genetic system for the analysis of murine B lymphocyte functional significance of Btk-SH2 domain in B-cell
signal transduction pathways dependent on Bruton's antigen receptor-coupled calcium signaling. Blood 94,
tyrosine kinase. Proc Natl Acad Sci U S A 97, 6687-6692 2357-2364 (1999)
(2000) 355. Fowell, D. J., K. Shinkai, X. C. Liao, A. M. Beebe, R.
343. Shan, X., M. J. Czar, S. C. Bunnell, P. Liu, Y. Liu, P. L. Coffman, D. R. Littman, & R. M. Locksley. Impaired
L. Schwartzberg, & R. L. Wange. Deficiency of PTEN in NFATc translocation and failure of Th2 development in
Jurkat T cells causes constitutive localization of Itk to the Itk- deficient CD4+ T cells. Immunity 11, 399-409 (1999)
plasma membrane and hyperresponsiveness to CD3 356. Perez-Villar, J. J., & S. B. Kanner. Regulated
stimulation. Mol Cell Biol 20, 6945-6957 (2000) association between the tyrosine kinase Emt/Itk/Tsk and
344. Mohamed, A. J., L. Vargas, B. F. Nore, C. M. phospholipase-C gamma 1 in human T lymphocytes. J
Backesjo, B. Christensson, & C. I. Smith. Immunol 163, 6435-6441 (1999)
Nucleocytoplasmic shuttling of Bruton's tyrosine kinase. J 357. Wang, D., J. Feng, R. Wen, J. C. Marine, M. Y.
Biol Chem 275, 40614-40619 (2000) Sangster, E. Parganas, A. Hoffmeyer, C. W. Jackson, J. L.
345. Perez-Villar, J. J., K. O'Day, D. H. Hewgill, S. G. Cleveland, P. J. Murray, & J. N. Ihle. Phospholipase
Nadler, & S. B. Kanner. Nuclear localization of the Cgamma2 is essential in the functions of B cell and several
tyrosine kinase Itk and interaction of its SH3 domain with Fc receptors. Immunity 13, 25-35 (2000)
karyopherin alpha (Rch1 alpha). Int Immunol 13, 1265- 358. Bunnell, S. C., M. Diehn, M. B. Yaffe, P. R. Findell,
1274 (2001) L. C. Cantley, & L. J. Berg. Biochemical interactions
346. de Weers, M., G. S. Brouns, S. Hinshelwood, C. integrating Itk with the T cell receptor- initiated signaling
Kinnon, R. K. Schuurman, R. W. Hendriks, & J. Borst. B- cascade. J Biol Chem 275, 2219-2230 (2000)
cell antigen receptor stimulation activates the human 359. Schneider, H., B. Guerette, C. Guntermann, & C. E.
Bruton's tyrosine kinase, which is deficient in X-linked Rudd. Resting lymphocyte kinase (Rlk/Txk) targets
agammaglobulinemia. Journal of Biological Chemistry lymphoid adaptor SLP-76 in the cooperative activation of
269, 23857-23860 (1994) interleukin-2 transcription in T-cells. J Biol Chem 275,
347. Aoki, Y., K. J. Isselbacher, & S. Pillai. Bruton 3835-3840 (2000)
tyrosine kinase is tyrosine phosphorylated and activated in 360. Watanabe, D., S. Hashimoto, M. Ishiai, M.
pre-B lymphocytes and receptor-ligated B cells. Proc Natl Matsushita, Y. Baba, T. Kishimoto, T. Kurosaki, & S.
Acad Sci USA 91, 10606-10609 (1994) Tsukada. Four tyrosine residues in phospholipase C-gamma
348. Kawakami, Y., L. Yao, T. Miura, S. Tsukada, O. N. 2, identified as Btk-dependent phosphorylation sites, are
Witte, & T. Kawakami. Tyrosine phosphorylation and required for B cell antigen receptor-coupled calcium
activation of Bruton tyrosine kinase upon Fc epsilon RI signaling. J Biol Chem 276, 38595-38601 (2001)
cross-linking. Molecular & Cellular Biology 14, 5108-5113 361. Rodriguez, R., M. Matsuda, O. Perisic, J. Bravo, A.
(1994) Paul, N. P. Jones, Y. Light, K. Swann, R. L. Williams, &
349. Gibson, S., A. August, Y. Kawakami, T. Kawakami, M. Katan. Tyrosine residues in phospholipase Cgamma 2
B. Dupont, & G. B. Mills. The EMT/ITK/TSK (EMT) essential for the enzyme function in B-cell signaling. J Biol
tyrosine kinase is activated during TCR signaling: LCK Chem 276, 47982-47992 (2001)
is required for optimal activation of EMT. Journal of 362. Yang, W. C., K. A. Ching, C. D. Tsoukas, & L. J.
Immunology 156, 2716-2722 (1996) Berg. Tec kinase signaling in T cells is regulated by
350. Takata, M., & T. Kurosaki. A role for Bruton's phosphatidylinositol 3-kinase and the Tec pleckstrin
tyrosine kinase in B cell antigen receptor-mediated homology domain. J Immunol 166, 387-395 (2001)
activation of phospholipase C-gamma 2. Journal of 363. August, A., S. Gibson, Y. Kawakami, T. Kawakami,
Experimental Medicine 184, 31-40 (1996) G. B. Mills, & B. Dupont. CD28 is associated with and
351. Fluckiger, A. C., Z. Li, R. M. Kato, M. I. Wahl, H. induces the immediate tyrosine phosphorylation and
D. Ochs, R. Longnecker, J. P. Kinet, O. N. Witte, A. M. activation of the Tec family kinase ITK/EMT in the human
Scharenberg, & D. J. Rawlings. Btk/Tec kinases Jurkat leukemic T-cell line. Proc Natl Acad Sci USA 91,
regulate sustained increases in intracellular Ca2+ 9347-9351 (1994)
following B-cell receptor activation. Embo J 17, 1973- 364. Yang, W. C., M. Ghiotto, B. Barbarat, & D. Olive.
1985 (1998) The role of Tec protein-tyrosine kinase in T cell signaling.
352. Scharenberg, A. M., O. El-Hillal, D. A. Fruman, L. Journal of Biological Chemistry 274, 607-617 (1999)
O. Beitz, Z. Li, S. Lin, I. Gout, L. C. Cantley, D. J. 365. Liao, X. C., S. Fournier, N. Killeen, A. Weiss, J. P.
Rawlings, & J. P. Kinet. Phosphatidylinositol-3,4,5- Allison, & D. R. Littman. Itk negatively regulates induction
trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent of T cell proliferation by CD28 costimulation. Journal of
calcium signaling pathway: a target for SHIP-mediated Experimental Medicine 186, 221-228 (1997)
inhibitory signals. Embo J 17, 1961-1972 (1998) 366. Yang, W. C., & D. Olive. Tec kinase is involved in
353. Su, Y. W., Y. Zhang, J. Schweikert, G. A. transcriptional regulation of IL-2 and IL-4 in the CD28
Koretzky, M. Reth, & J. Wienands. Interaction of SLP pathway. Eur J Immunol 29, 1842-1849 (1999)
adaptors with the SH2 domain of Tec family kinases. 367. Michel, F., G. Attal-Bonnefoy, G. Mangino, S. Mise-
Eur J Immunol 29, 3702-3711 (1999) Omata, & O. Acuto. CD28 as a molecular amplifier

623
Non-receptor protein tyrosine kinases

extending TCR ligation and signaling capabilities. Etk/BMX alone is sufficient to transactivate STAT-
Immunity 15, 935-945 (2001) mediated gene expression in salivary and lung epithelial
368. Mano, H., Y. Yamashita, K. Sato, Y. Yazaki, & H. cells. J Biol Chem 274, 38204-38210 (1999)
Hirai. Tec protein-tyrosine kinase is involved in 382. Tsai, Y. T., Y. H. Su, S. S. Fang, T. N. Huang, Y.
interleukin-3 signaling pathway. Blood 85, 343-350 (1995) Qiu, Y. S. Jou, H. M. Shih, H. J. Kung, & R. H. Chen. Etk,
369. Matsuda, T., M. Takahashi-Tezuka, T. Fukada, Y. a Btk family tyrosine kinase, mediates cellular
Okuyama, Y. Fujitani, S. Tsukada, H. Mano, H. Hirai, O. transformation by linking Src to STAT3 activation. Mol
N. Witte, & T. Hirano. Association and activation of Btk Cell Biol 20, 2043-2054 (2000)
and Tec tyrosine kinases by gp130, a signal transducer of 383. Nore, B. F., L. Vargas, A. J. Mohamed, L. J. Branden,
the interleukin-6 family of cytokines. Blood 85, 627-633 C. M. Backesjo, T. C. Islam, P. T. Mattsson, K. Hultenby,
(1995) B. Christensson, & C. I. Smith. Redistribution of Bruton's
370. Machide, M., H. Mano, & K. Todokoro. Interleukin 3 tyrosine kinase by activation of phosphatidylinositol 3-
and erythropoietin induce association of Vav with Tec kinase and Rho-family GTPases. Eur J Immunol 30, 145-
kinase through Tec homology domain. Oncogene 11, 619- 154 (2000)
625 (1995) 384. Woods, M. L., W. J. Kivens, M. A. Adelsman, Y.
371. Ekman, N., E. Arighi, I. Rajantie, P. Saharinen, A. Qiu, A. August, & Y. Shimizu. A novel function for the
Ristimaki, O. Silvennoinen, & K. Alitalo. The Bmx Tec family tyrosine kinase Itk in activation of beta 1
tyrosine kinase is activated by IL-3 and G-CSF in a PI-3K integrins by the T-cell receptor. Embo J 20, 1232-1244
dependent manner. Oncogene 19, 4151-4158 (2000) (2001)
372. Mao, J., W. Xie, H. Yuan, M. I. Simon, H. Mano, & 385. Vetrie, D., I. Vorechovsky, P. Sideras, J. Holland, A.
D. Wu. Tec/Bmx non-receptor tyrosine kinases are Davies, F. Flinter, L. Hammarstrom, C. Kinnon, R.
involved in regulation of Rho and serum response factor by Levinsky, M. Bobrow, C. I. E. Smith, & D. R. Bentley. The
Galpha12/13. Embo J 17, 5638-5646 (1998) gene involved in X-linked agammaglobulinaemia is a
373. Hamazaki, Y., H. Kojima, H. Mano, Y. Nagata, K. member of the Src family of protein-tyrosine kinases.
Todokoro, T. Abe, & T. Nagasawa. Tec is involved in G Nature 361, 226-233 (1993)
protein-coupled receptor- and integrin-mediated signalings 386. Tsukada, S., D. C. Saffran, D. J. Rawlings, O.
in human blood platelets. Oncogene 16, 2773-2779 (1998) Parolini, R. C. Allen, I. Klisak, R. S. Sparkes, H.
374. Laffargue, M., L. Monnereau, J. Tuech, A. Ragab, J. Kubagawa, T. Mohandas, S. Quan, J. W. Belmont, M. D.
Ragab-Thomas, B. Payrastre, P. Raynal, & H. Chap. Cooper, M. E. Conley, & O. N. Witte. Deficient expression
Integrin-dependent tyrosine phoshorylation and of a B-cell cytoplasmic tyrosine Kinase in human X-linked
cytoskeletal translocation of Tec in thrombin-activated agammaglobulinemia. Cell 72, 279-290 (1993)
platelets. Biochem Biophys Res Commun 238, 247-251 387. Khan, W. N., F. W. Alt, R. M. Gerstein, B. A.
(1997) Malynn, I. Larsson, G. Rathbun, L. Davidson, S. Muller, A.
375. Bajpai, U. D., K. Zhang, M. Teutsch, R. Sen, & H. H. B. Kantor, L. A. Herzenberg, & et al. Defective B cell
Wortis. Bruton's tyrosine kinase links the B cell receptor to development and function in Btk-deficient mice. Immunity
nuclear factor kappaB activation. J Exp Med 191, 1735- 3, 283-299 (1995)
1744 (2000) 388. Ellmeier, W., S. Jung, M. J. Sunshine, F. Hatam, Y.
376. Petro, J. B., & W. N. Khan. Phospholipase C-gamma Xu, D. Baltimore, H. Mano, & D. R. Littman. Severe B cell
2 couples Bruton's tyrosine kinase to the NF-kappaB deficiency in mice lacking the Tec kinase family members
signaling pathway in B lymphocytes. J Biol Chem 276, Tec and Btk. J Exp Med 192, 1611-1624 (2000)
1715-1719 (2001) 389. Liao, X. C., & D. R. Littman. Altered T cell receptor
377. Tan, J. E., S. C. Wong, S. K. Gan, S. Xu, & K. P. signaling and disrupted T cell development in mice lacking
Lam. The adaptor protein BLNK is required for b cell Itk. Immunity 3, 757-769 (1995)
antigen receptor-induced activation of nuclear factor-kappa 390. Schaeffer, E. M., J. Debnath, G. Yap, D. McVicar, X.
B and cell cycle entry and survival of B lymphocytes. J C. Liao, D. R. Littman, A. Sher, H. E. Varmus, M. J.
Biol Chem 276, 20055-20063 (2001) Lenardo, & P. L. Schwartzberg. Requirement for Tec
378. Craxton, A., A. Jiang, T. Kurosaki, & E. A. Clark. kinases Rlk and Itk in T cell receptor signaling and
Syk and Bruton's tyrosine kinase are required for B cell immunity. Science 284, 638-641 (1999)
antigen receptor-mediated activation of the kinase Akt. J 391. Rajantie, I., N. Ekman, K. Iljin, E. Arighi, Y. Gunji, J.
Biol Chem 274, 30644-30650 (1999) Kaukonen, A. Palotie, M. Dewerchin, P. Carmeliet, & K.
379. Saharinen, P., N. Ekman, K. Sarvas, P. Parker, K. Alitalo. Bmx tyrosine kinase has a redundant function
Alitalo, & O. Silvennoinen. The Bmx tyrosine kinase downstream of angiopoietin and vascular endothelial
induces activation of the Stat signaling pathway, which is growth factor receptors in arterial endothelium. Mol Cell
specifically inhibited by protein kinase Cdelta. Blood 90, Biol 21, 4647-4655 (2001)
4341-4353 (1997) 392. Andreotti, A. H., S. C. Bunnell, S. Feng, L. J. Berg,
380. Yamashita, Y., S. Watanabe, A. Miyazato, K. Ohya, & S. L. Schreiber. Regulatory intramolecular association
U. Ikeda, K. Shimada, N. Komatsu, K. Hatake, Y. Miura, in a tyrosine kinase of the Tec family. Nature 385, 93-97
K. Ozawa, & H. Mano. Tec and Jak2 kinases cooperate to (1997)
mediate cytokine-driven activation of c-fos transcription. 393. Hansson, H., M. P. Okoh, C. I. Smith, M. Vihinen,
Blood 91, 1496-1507 (1998) & T. Hard. Intermolecular interactions between the SH3
381. Wen, X., H. H. Lin, H. M. Shih, H. J. Kung, & D. K. domain and the proline-rich TH region of Bruton's
Ann. Kinase activation of the non-receptor tyrosine kinase tyrosine kinase. FEBS Lett 489, 67-70 (2001)

624
Non-receptor protein tyrosine kinases

394. Laederach, A., K. W. Cradic, K. N. Brazin, J. mechanism initiated by SRC family kinases. Science 271,
Zamoon, D. B. Fulton, X. Y. Huang, & A. H. Andreotti. 822-825 (1996)
Competing modes of self-association in the regulatory 406. Afar, D. E., H. Park, B. W. Howell, D. J. Rawlings, J.
domains of Bruton's tyrosine kinase: intramolecular contact Cooper, & O. N. Witte. Regulation of Btk by Src family
versus asymmetric homodimerization. Protein Sci 11, 36- tyrosine kinases. Molecular & Cellular Biology 16, 3465-
45 (2002) 3471 (1996)
395. Pursglove, S. E., T. D. Mulhern, J. P. Mackay, M. G. 407. Heyeck, S. D., H. M. Wilcox, S. C. Bunnell, & L. J.
Hinds, & G. W. Booker. The solution structure and Berg. Lck phosphorylates the activation loop tyrosine of
intramolecular associations of the Tec kinase SRC the Itk kinase domain and activates Itk kinase activity. J
homology 3 domain. J Biol Chem 277, 755-762 (2002) Biol Chem 272, 25401-25408 (1997)
396. Yamashita, Y., A. Miyazato, K. Ohya, U. Ikeda, K. 408. Park, H., M. I. Wahl, D. E. Afar, C. W. Turck, D. J.
Shimada, Y. Miura, K. Ozawa, & H. Mano. Deletion of Src Rawlings, C. Tam, A. M. Scharenberg, J. P. Kinet, & O. N.
homology 3 domain results in constitutive activation of Tec Witte. Regulation of Btk function by a major
protein-tyrosine kinase. Jpn J Cancer Res 87, 1106-1110 autophosphorylation site within the SH3 domain. Immunity
(1996) 4, 515-525 (1996)
397. Li, Z., M. I. Wahl, A. Eguinoa, L. R. Stephens, P. T. 409. Rane, S. G., & E. P. Reddy. Janus kinases:
Hawkins, & O. N. Witte. Phosphatidylinositol 3-kinase- components of multiple signaling pathways. Oncogene 19,
gamma activates Bruton's tyrosine kinase in concert with 5662-5679 (2000)
Src family kinases. Proceedings of the National Academy 410. Rane, S. G., & E. P. Reddy. JAKs, STATs and Src
of Sciences of the United States of America 94, 13820- kinases in hematopoiesis. Oncogene 21, 3334-3358 (2002)
13825 (1997) 411. Witthuhn, B. A., F. W. Quelle, O. Silvennoinen, T.
398. August, A., A. Sadra, B. Dupont, & H. Hanafusa. Src- Yi, B. Tang, O. Miura, & J. N. Ihle. JAK2 associates with
induced activation of inducible T cell kinase (ITK) requires the erythropoietin receptor and is tyrosine phosphorylated
phosphatidylinositol 3-kinase activity and the Pleckstrin and activated following stimulation with erythropoietin.
homology domain of inducible T cell kinase. Proceedings Cell 74, 227-236 (1993)
of the National Academy of Sciences of the United States of 412. Argetsinger, L. S., G. S. Campbell, X. Yang, B. A.
America 94, 11227-11232 (1997) Witthuhn, O. Silvennoinen, J. N. Ihle, & C. Carter-Su.
399. Qiu, Y., D. Robinson, T. G. Pretlow, & H. J. Kung. Identification of JAK2 as a growth hormone receptor-
Etk/Bmx, a tyrosine kinase with a pleckstrin-homology associated tyrosine kinase. Cell 74, 237-244 (1993)
domain, is an effector of phosphatidylinositol 3'-kinase and 413. Igarashi, K., G. Garotta, L. Ozmen, A. Ziemiecki, A.
is involved in interleukin 6-induced neuroendocrine F. Wilks, A. G. Harpur, A. C. Larner, & D. S. Finbloom.
differentiation of prostate cancer cells. Proceedings of the Interferon-gamma induces tyrosine phosphorylation of
National Academy of Sciences of the United States of interferon-gamma receptor and regulated association of
America 95, 3644-3649 (1998) protein tyrosine kinases, Jak1 and Jak2, with its receptor. J
400. Lu, Y., B. Cuevas, S. Gibson, H. Khan, R. LaPushin, Biol Chem 269, 14333-14336 (1994)
J. Imboden, & G. B. Mills. Phosphatidylinositol 3-kinase is 414. Nicholson, S. E., A. C. Oates, A. G. Harpur, A.
required for CD28 but not CD3 regulation of the TEC Ziemiecki, A. F. Wilks, & J. E. Layton. Tyrosine kinase
family tyrosine kinase EMT/ITK/TSK: functional and JAK1 is associated with the granulocyte-colony-stimulating
physical interaction of EMT with phosphatidylinositol 3- factor receptor and both become tyrosine-phosphorylated
kinase. Journal of Immunology 161, 5404-5412 (1998) after receptor activation. Proc Natl Acad Sci USA 91, 2985-
401. Li, T., D. J. Rawlings, H. Park, R. M. Kato, O. N. 2988 (1994)
Witte, & A. B. Satterthwaite. Constitutive membrane 415. Lutticken, C., U. M. Wegenka, J. P. Yuan, J.
association potentiates activation of Bruton tyrosine kinase. Buschmann, C. Schindler, A. Ziemiecki, A. G. Harpur, A.
Oncogene 15, 1375-1383 (1997) F. Wilks, K. Yasukawa, T. Taga, T. Kishimoto, G.
402. Yoshida, K., Y. Yamashita, A. Miyazato, K. Ohya, A. Barbieri, S. Pellegrini, M. Sendtner, P. C. Heinrich, & F.
Kitanaka, U. Ikeda, K. Shimada, T. Yamanaka, K. Ozawa, Horn. Association of transcription factor APRF and protein
& H. Mano. Mediation by the protein-tyrosine kinase Tec kinase Jak1 with the interleukin-6 signal transducer gp130.
of signaling between the B cell antigen receptor and Dok-1. Science 263, 89-92 (1994)
J Biol Chem 275, 24945-24952 (2000) 416. Stahl, N., T. G. Boulton, T. Farruggella, N. Y. Ip, S.
403. Gibson, S., A. August, D. Branch, B. Dupont, & G. Davis, B. A. Witthuhn, F. W. Quelle, O. Silvennoinen, G.
M. Mills. Functional LCK Is required for optimal CD28- Barbieri, S. Pellegrini, J. N. Ihle, & G. D. Yancopoulos.
mediated activation of the TEC family tyrosine kinase Association and activation of Jak-Tyk kinases by CNTF-
EMT/ITK. Journal of Biological Chemistry 271, 7079- LIF-OSM-IL-6 beta-receptor components. Science 263, 92-
7083 (1996) 95 (1994)
404. Mano, H., Y. Yamashita, A. Miyazato, Y. Miura, & 417. Colamonici, O. R., H. Uyttendaele, P. Domanski, H.
K. Ozawa. Tec protein-tyrosine kinase is an effector Yan, & J. J. Krolewski. p135(tyk2), an interferon-alpha-
molecule of Lyn protein-tyrosine kinase. FASEB Journal activated tyrosine kinase, is physically associated with an
10, 637-642 (1996) interferon-alpha receptor. J Biol Chem 269, 3518-3522 (1994)
405. Rawlings, D. J., A. M. Scharenberg, H. Park, M. I. 418. Vanderkuur, J. A., X. Y. Wang, L. Y. Zhang, G. S.
Wahl, S. Lin, R. M. Kato, A. C. Fluckiger, O. N. Witte, & Campbell, G. Allevato, N. Billestrup, G. Norsted, & C.
J. P. Kinet. Activation of BTK by a phosphorylation Cartersu. Domains of the growth hormone receptor

625
Non-receptor protein tyrosine kinases

required for association and activation of JAK2 tyrosine 430. Silvennoinen, O., J. N. Ihle, J. Schlessinger, & D. E.
kinase. J Biol Chem 269, 21709-21717 (1994) Levy. Interferon-induced nuclear signalling by Jak protein
419. Colamonici, O., H. Yan, P. Domanski, R. Handa, D. tyrosine kinases. Nature 366, 583-585 (1993)
Smalley, J. Mullersman, M. Witte, K. Krishnan, & J. 431. Witthuhn, B. A., O. Silvennoinen, O. Miura, K. S.
Krolewski. Direct binding to and tyrosine phosphorylation Lai, C. Cwik, E. T. Liu, & J. N. Ihle. Involvement of the
of the alpha subunit of the type I interferon receptor by Jak-3 Janus kinase in signalling by interleukins 2 and 4 in
p135tyk2 tyrosine kinase. Mol Cell Biol 14, 8133-8142 lymphoid and myeloid cells. Nature 370, 153-157 (1994)
(1994) 432. Quelle, F. W., N. Sato, B. S. Witthuhn, R. C. Inhorn,
420. Zhao, Y., F. Wagner, S. J. Frank, & A. S. Kraft. The M. Eder, A. Miyajima, J. D. Griffin, & J. N. Ihle. JAK2
amino-terminal portion of the JAK2 protein kinase is associates with the beta(C) chain of the receptor far
necessary for binding and phosphorylation of the granulocyte-macrophage colony-stimulating factor, and its
granulocyte-macrophage colony- stimulating factor activation requires the membrane-proximal region. Mol
receptor beta c chain. J Biol Chem 270, 13814-13818 Cell Biol 14, 4335-4341 (1994)
(1995) 433. Barbieri, G., L. Velazquez, M. Scrobogna, M.
421. Frank, S. J., W. Yi, Y. Zhao, J. F. Goldsmith, G. Fellous, & S. Pellegrini. Activation of the protein tyrosine
Gilliland, J. Jiang, I. Sakai, & A. S. Kraft. Regions of the kinase tyk2 by interferon alpha/beta. Eur J Biochem 223,
JAK2 tyrosine kinase required for coupling to the growth 427-435 (1994)
hormone receptor. J Biol Chem 270, 14776-14785 (1995) 434. Shimoda, K., H. Iwasaki, S. Okamura, Y. Ohno, A.
422. Kohlhuber, F., N. C. Rogers, D. Watling, J. Feng, D. Kubota, F. Arima, T. Otsuka, & Y. Niho. G-CSF induces
Guschin, J. Briscoe, B. A. Witthuhn, S. V. Kotenko, S. tyrosine phosphorylation of the JAK2 protein in the human
Pestka, G. R. Stark, J. N. Ihle, & I. M. Kerr. A JAK1/JAK2 myeloid G-CSF responsive and proliferative cells, but not
chimera can sustain alpha and gamma interferon responses. in mature neutrophils. Biochem Biophys Res Commun 203,
Mol Cell Biol 17, 695-706 (1997) 922-928 (1994)
423. Gauzzi, M. C., G. Barbieri, M. F. Richter, G. Uze, L. 435. Zeng, Y. X., H. Takahashi, M. Shibata, & K.
Ling, M. Fellous, & S. Pellegrini. The amino-terminal Hirokawa. JAK3 janus kinase is involved in interleukin 7
region of Tyk2 sustains the level of interferon alpha signal pathway. FEBS Lett 353, 289-293 (1994)
receptor 1, a component of the interferon alpha/beta 436. Tanaka, N., H. Asao, K. Ohbo, N. Ishii, T. Takeshita,
receptor. Proc Natl Acad Sci U S A 94, 11839-11844 M. Nakamura, H. Sasaki, & K. Sugamura. Physical
(1997) association of JAK1 and JAK2 tyrosine kinases with the
424. Chen, M., A. Cheng, Y. Q. Chen, A. Hymel, E. P. interleukin 2 receptor beta and gamma chains. Proc Natl
Hanson, L. Kimmel, Y. Minami, T. Taniguchi, P. S. Acad Sci USA 91, 7271-7275 (1994)
Changelian, & J. J. O'Shea. The amino terminus of JAK3 is 437. Kirken, R. A., H. Rui, M. G. Malabarba, & W. L.
necessary and sufficient for binding to the common gamma Farrar. Identification of interleukin-2 receptor-associated
chain and confers the ability to transmit interleukin 2- tyrosine kinase p116 as novel leukocyte-specific Janus
mediated signals. Proc Natl Acad Sci U S A 94, 6910-6915 kinase. J Biol Chem 269, 19136-19141 (1994)
(1997) 438. Johnston, J. A., M. Kawamura, R. A. Kirken, Y. Q.
425. Cacalano, N. A., T. S. Migone, F. Bazan, E. P. Chen, T. B. Blake, K. Shibuya, J. R. Ortaldo, D. W.
Hanson, M. Chen, F. Candotti, J. J. O'Shea, & J. A. McVicar, & J. J. O'Shea. Phosphorylation and activation of
Johnston. Autosomal SCID caused by a point mutation in the Jak-3 Janus kinase in response to interleukin-2. Nature
the N-terminus of Jak3: mapping of the Jak3-receptor 370, 151-153 (1994)
interaction domain. Embo J 18, 1549-1558 (1999) 439. Yin, T., M. L. Tsang, & Y. C. Yang. JAK1 kinase
426. Velazquez, L., M. Fellous, G. R. Stark, & S. forms complexes with interleukin-4 receptor and
Pellegrini. A protein tyrosine kinase in the interferon 4PS/insulin receptor substrate-1-like protein and is
alpha/beta signaling pathway. Cell 70, 313-322 (1992) activated by interleukin-4 and interleukin-9 in T
427. Silvennoinen, O., B. A. Witthuhn, F. W. Quelle, J. L. lymphocytes. J Biol Chem 269, 26614-26617 (1994)
Cleveland, T. Yi, & J. N. Ihle. Structure of the murine Jak2 440. Narazaki, M., B. A. Witthuhn, K. Yoshida, O.
protein-tyrosine kinase and its role in interleukin 3 signal Silvennoinen, K. Yasukawa, J. N. Ihle, T. Kishimoto, & T.
transduction. Proc Natl Acad Sci U S A 90, 8429-8433 Taga. Activation of JAK2 kinase mediated by the
(1993) interleukin 6 signal transducer gp130. Proc Natl Acad Sci
428. Muller, M., J. Briscoe, C. Laxton, D. Guschin, A. U S A 91, 2285-2289 (1994)
Ziemiecki, O. Silvennoinen, A. G. Harpur, G. Barbieri, B. 441. Dusanterfourt, I., O. Muller, A. Ziemiecki, P.
A. Witthuhn, C. Schindler, S. Pellegrini, A. F. Wilks, J. N. Mayeux, B. Drucker, J. Djiane, A. Wilks, A. G. Harpur, S.
Ihle, G. R. Stark, & I. M. Kerr. The protein tyrosine kinase Fischer, & S. Gisselbrecht. Identification of JAK protein
JAK1 complements defects in interferon-alpha/beta and - tyrosine kinases as signaling molecules for prolactin.
gamma signal transduction. Nature 366, 129-135 (1993) Functional analysis of prolactin receptor and prolactin
429. Watling, D., D. Guschin, M. Muller, O. Silvennoinen, erythropoietin receptor chimera expressed in lymphoid
B. A. Witthuhn, F. W. Quelle, N. C. Rogers, C. Schindler, cells. EMBO J 13, 2583-2591 (1994)
G. R. Stark, J. N. Ihle, & I. M. Kerr. Complementation by 442. Foxwell, B. M., C. Beadling, D. Guschin, I. Kerr, &
the protein tyrosine kinase JAK2 of a mutant cell line D. Cantrell. Interleukin-7 can induce the activation of Jak
defective in the interferon-gamma signal transduction 1, Jak 3 and STAT 5 proteins in murine T cells. Eur J
pathway. Nature 366, 166-170 (1993) Immunol 25, 3041-3046 (1995)

626
Non-receptor protein tyrosine kinases

443. Guschin, D., N. Rogers, J. Briscoe, B. Witthuhn, D. with autosomal severe combined immune deficiency
Watling, F. Horn, S. Pellegrini, K. Yasukawa, P. Heinrich, (SCID). Nature 377, 65-68 (1995)
G. R. Stark, J. N. Ihle, & I. M. Kerr. A major role for the 457. Gauzzi, M. C., L. Velazquez, R. McKendry, K. E.
protein tyrosine kinase JAK1 in the JAK/STAT signal Mogensen, M. Fellous, & S. Pellegrini. Interferon-alpha-
transduction pathway in response to interleukin-6. Embo J dependent activation of Tyk2 requires phosphorylation of
14, 1421-1429 (1995) positive regulatory tyrosines by another kinase. J Biol
444. Bacon, C. M., D. W. McVicar, J. R. Ortaldo, R. C. Chem 271, 20494-20500 (1996)
Rees, J. J. O'Shea, & J. A. Johnston. Interleukin 12 (IL-12) 458. Zhou, Y. J., E. P. Hanson, Y. Q. Chen, K. Magnuson,
induces tyrosine phosphorylation of JAK2 and TYK2: M. Chen, P. G. Swann, R. L. Wange, P. S. Changelian, & J.
differential use of Janus family tyrosine kinases by IL-2 J. O'Shea. Distinct tyrosine phosphorylation sites in JAK3
and IL-12. J Exp Med 181, 399-404 (1995) kinase domain positively and negatively regulate its
445. Leonard, W. J. Role of Jak kinases and STATs in enzymatic activity. Proc Natl Acad Sci U S A 94, 13850-
cytokine signal transduction. Int J Hematol 73, 271-277 13855 (1997)
(2001) 459. Liu, K. D., S. L. Gaffen, M. A. Goldsmith, & W. C.
446. O'Shea, J. J., M. Gadina, & R. D. Schreiber. Cytokine Greene. Janus kinases in interleukin-2-mediated signaling:
signaling in 2002: new surprises in the Jak/Stat pathway. JAK1 and JAK3 are differentially regulated by tyrosine
Cell 109, S121-131 (2002) phosphorylation. Curr Biol 7, 817-826 (1997)
447. Aaronson, D. S., & C. M. Horvath. A road map for 460. David, M., H. E. Chen, S. Goelz, A. C. Larner, & B.
those who know JAK-STAT. Science 296, 1653-1655 G. Neel. Differential regulation of the alpha/beta
(2002) interferon-stimulated Jak/Stat pathway by the SH2 domain-
448. Kazansky, A. V., E. B. Kabotyanski, S. L. containing tyrosine phosphatase SHPTP1. Mol Cell Biol
Wyszomierski, M. A. Mancini, & J. M. Rosen. Differential 15, 7050-7058 (1995)
effects of prolactin and src/abl kinases on the nuclear 461. Jiao, H., K. Berrada, W. Yang, M. Tabrizi, L. C.
translocation of STAT5B and STAT5A. J Biol Chem 274, Platanias, & T. Yi. Direct association with and
22484-22492 (1999) dephosphorylation of Jak2 kinase by the SH2- domain-
449. Rodig, S. J., M. A. Meraz, J. M. White, P. A. Lampe, containing protein tyrosine phosphatase SHP-1. Mol Cell
J. K. Riley, C. D. Arthur, K. L. King, K. C. Sheehan, L. Biol 16, 6985-6992 (1996)
Yin, D. Pennica, E. M. Johnson, Jr., & R. D. Schreiber. 462. Yin, T., R. Shen, G. S. Feng, & Y. C. Yang.
Disruption of the Jak1 gene demonstrates obligatory and Molecular characterization of specific interactions between
nonredundant roles of the Jaks in cytokine-induced biologic SHP-2 phosphatase and JAK tyrosine kinases. J Biol Chem
responses. Cell 93, 373-383 (1998) 272, 1032-1037 (1997)
450. Neubauer, H., A. Cumano, M. Muller, H. Wu, U. 463. Haque, S. J., P. Harbor, M. Tabrizi, T. Yi, & B. R.
Huffstadt, & K. Pfeffer. Jak2 deficiency defines an Williams. Protein-tyrosine phosphatase Shp-1 is a negative
essential developmental checkpoint in definitive regulator of IL-4- and IL-13-dependent signal transduction.
hematopoiesis. Cell 93, 397-409 (1998) J Biol Chem 273, 33893-33896 (1998)
451. Parganas, E., D. Wang, D. Stravopodis, D. J. 464. You, M., D. H. Yu, & G. S. Feng. Shp-2 tyrosine
Topham, J. C. Marine, S. Teglund, E. F. Vanin, S. Bodner, phosphatase functions as a negative regulator of the
O. R. Colamonici, J. M. van Deursen, G. Grosveld, & J. N. interferon-stimulated Jak/STAT pathway. Mol Cell Biol 19,
Ihle. Jak2 is essential for signaling through a variety of 2416-2424 (1999)
cytokine receptors. Cell 93, 385-395 (1998) 465. Tanuma, N., K. Nakamura, H. Shima, & K. Kikuchi.
452. Park, S. Y., K. Saijo, T. Takahashi, M. Osawa, H. Protein-tyrosine phosphatase PTPepsilon C inhibits Jak-
Arase, N. Hirayama, K. Miyake, H. Nakauchi, T. STAT signaling and differentiation induced by interleukin-
Shirasawa, & T. Saito. Developmental defects of lymphoid 6 and leukemia inhibitory factor in M1 leukemia cells. J
cells in Jak3 kinase-deficient mice. Immunity 3, 771-782 Biol Chem 275, 28216-28221 (2000)
(1995) 466. Simoncic, P. D., A. Lee-Loy, D. L. Barber, M. L.
453. Nosaka, T., J. M. van Deursen, R. A. Tripp, W. E. Tremblay, & C. J. McGlade. The T cell protein tyrosine
Thierfelder, B. A. Witthuhn, A. P. McMickle, P. C. phosphatase is a negative regulator of Janus family kinases
Doherty, G. C. Grosveld, & J. N. Ihle. Defective lymphoid 1 and 3. Curr Biol 12, 446-453 (2002)
development in mice lacking Jak3. Science 270, 800-802 467. Yu, C. L., & S. J. Burakoff. Involvement of
(1995) proteasomes in regulating Jak-STAT pathways upon
454. Thomis, D. C., C. B. Gurniak, E. Tivol, A. H. Sharpe, interleukin-2 stimulation. J Biol Chem 272, 14017-14020
& L. J. Berg. Defects in B lymphocyte maturation and T (1997)
lymphocyte activation in mice lacking Jak3. Science 270, 468. Callus, B. A., & B. Mathey-Prevot. Interleukin-3-
794-797 (1995) induced activation of the JAK/STAT pathway is prolonged
455. Grossman, W. J., J. W. Verbsky, L. Yang, L. J. Berg, by proteasome inhibitors. Blood 91, 3182-3192 (1998)
L. E. Fields, D. D. Chaplin, & L. Ratner. Dysregulated 469. Krebs, D. L., & D. J. Hilton. SOCS: physiological
myelopoiesis in mice lacking Jak3. Blood 94, 932-939 suppressors of cytokine signaling. J Cell Sci 113, 2813-
(1999) 2819 (2000)
456. Macchi, P., A. Villa, S. Giliani, M. G. Sacco, A. 470. Duhe, R. J., L. H. Wang, & W. L. Farrar. Negative
Frattini, F. Porta, A. G. Ugazio, J. A. Johnston, F. Candotti, regulation of Janus kinases. Cell Biochem Biophys 34, 17-
J. J. O'Shea, & et al. Mutations of Jak-3 gene in patients 59 (2001)

627
Non-receptor protein tyrosine kinases

471. Hanks, S. K., M. B. Calalb, M. C. Harper, & S. K. focal adhesion kinase. Molecular Biology of the Cell 6,
Patel. Focal adhesion protein-tyrosine kinase 637-647 (1995)
phosphorylated in response to cell attachment to 484. Sieg, D. J., C. R. Hauck, & D. D. Schlaepfer.
fibronectin. Proc. Natl. Acad. Sci. USA 89, 8487-8491 Required role of focal adhesion kinase (FAK) for integrin-
(1992) stimulated cell migration. J Cell Sci 112, 2677-2691 (1999)
472. Kornberg, L., H. S. Earp, J. T. Parsons, M. Schaller, 485. Thomas, J. W., M. A. Cooley, J. M. Broome, R.
& R. L. Juliano. Cell adhesion or integrin clustering Salgia, J. D. Griffin, C. R. Lombardo, & M. D. Schaller.
increases phosphorylation of a focal adhesion-associated The role of focal adhesion kinase binding in the regulation
tyrosine kinase. J Biol Chem 267, 23439-23442 (1992) of tyrosine phosphorylation of paxillin. J Biol Chem 274,
473. Lipfert, L., B. Haimovich, M. D. Schaller, B. S. 36684-36692 (1999)
Cobb, J. T. Parsons, & J. S. Brugge. Integrin-dependent 486. Tachibana, K., T. Sato, N. D'Avirro, & C. Morimoto.
phosphorylation and activation of the protein tyrosine Direct association of pp125FAK with paxillin, the focal
kinase pp125FAK in platelets. Journal of Cell Biology 119, adhesion-targeting mechanism of pp125FAK. Journal of
905-912 (1992) Experimental Medicine 182, 1089-1099 (1995)
474. Schaller, M. D., C. A. Borgman, B. S. Cobb, R. R. 487. Cooley, M. A., J. M. Broome, C. Ohngemach, L. H.
Vines, A. B. Reynolds, & J. T. Parsons. pp125FAK a Romer, & M. D. Schaller. Paxillin binding is not the sole
structurally distinctive protein-tyrosine kinase associated determinant of focal adhesion localization or dominant-
with focal adhesions. Proceedings of the National Academy negative activity of focal adhesion kinase/focal adhesion
of Sciences of the United States of America 89, 5192-5196 kinase-related nonkinase. Mol Biol Cell 11, 3247-3263
(1992) (2000)
475. Whitney, G. S., P. Y. Chan, J. Blake, W. L. Cosand, 488. Zheng, C., Z. Xing, Z. C. Bian, C. Guo, A. Akbay, L.
M. G. Neubauer, A. Aruffo, & S. B. Kanner. Human T and Warner, & J. L. Guan. Differential regulation of Pyk2 and
B lymphocytes express a structurally conserved focal focal adhesion kinase (FAK). The C- terminal domain of
adhesion kinase, pp125FAK. DNA & Cell Biology 12, 823- FAK confers response to cell adhesion. J Biol Chem 273,
830 (1993) 2384-2389 (1998)
476. Avraham, S., R. London, Y. Fu, S. Ota, D. 489. Polte, T. R., & S. K. Hanks. Interaction between focal
Hiregowdara, J. Li, S. Jiang, L. M. Pasztor, R. A. White, J. adhesion kinase and Crk-associated tyrosine kinase
E. Groopman, & H. Avraham. Identification and substrate p130Cas. Proceedings of the National Academy of
characterization of a novel related adhesion focal tyrosine Sciences of the United States of America 92, 10678-10682
kinase (RAFTK) from megakaryocytes and brain. Journal (1995)
of Biological Chemistry 270, 27742-27751 (1995) 490. Harte, M. T., J. D. Hildebrand, M. R. Burnham, A. H.
477. Lev, S., H. Moreno, R. Martinez, P. Canoll, E. Peles, Bouton, & J. T. Parsons. p130Cas, a substrate associated
J. M. Musacchio, G. D. Plowman, B. Rudy, & J. with v-Src and v-Crk, localizes to focal adhesions and
Schlessinger. Protein tyrosine kinase PYK2 involved in binds to focal adhesion kinase. Journal of Biological
Ca(2+)-induced regulation of ion channel and MAP kinase Chemistry 271, 13649-13655 (1996)
functions. Nature 376, 737-745 (1995) 491. Polte, T. R., & S. K. Hanks. Complexes of focal
478. Sasaki, H., K. Nagura, M. Ishino, H. Tobioka, K. adhesion kinase (FAK) and Crk-associated substrate
Kotani, & T. Sasaki. Cloning and characterization of cell (p130(Cas)) are elevated in cytoskeleton-associated
adhesion kinase beta, a novel protein-tyrosine kinase of the fractions following adhesion and Src transformation.
focal adhesion kinase subfamily. Journal of Biological Requirements for Src kinase activity and FAK proline-rich
Chemistry 270, 21206-21219 (1995) motifs. Journal of Biological Chemistry 272, 5501-5509
479. Schaller, M. D., C. A. Otey, J. D. Hildebrand, & J. T. (1997)
Parsons. Focal adhesion kinase and paxillin bind to 492. Astier, A., H. Avraham, S. N. Manie, J. Groopman, T.
peptides mimicking beta integrin cytoplasmic domains. Canty, S. Avraham, & A. S. Freedman. The related adhesion
Journal of Cell Biology 130, 1181-1187 (1995) focal tyrosine kinase is tyrosine-phosphorylated after beta1-
480. Danker, K., B. Gabriel, C. Heidrich, & W. Reutter. integrin stimulation in B cells and binds to p130cas. Journal of
Focal adhesion kinase pp125FAK and the beta 1 integrin Biological Chemistry 272, 228-232 (1997)
subunit are constitutively complexed in HaCaT cells. 493. Xiong, W. C., M. Macklem, & J. T. Parsons.
Experimental Cell Research 239, 326-331 (1998) Expression and characterization of splice variants of PYK2,
481. Sieg, D. J., C. R. Hauck, D. Ilic, C. K. Klingbeil, E. a focal adhesion kinase-related protein. J Cell Sci 111,
Schaefer, C. H. Damsky, & D. D. Schlaepfer. FAK 1981-1991 (1998)
integrates growth-factor and integrin signals to promote 494. Dikic, I., & J. Schlessinger. Identification of a new
cell migration. Nat Cell Biol 2, 249-256 (2000) Pyk2 isoform implicated in chemokine and antigen receptor
482. Chen, R., O. Kim, M. Li, X. Xiong, J. L. Guan, H. J. signaling. J Biol Chem 273, 14301-14308 (1998)
Kung, H. Chen, Y. Shimizu, & Y. Qiu. Regulation of the 495. Schaller, M. D., & T. Sasaki. Differential signaling by
PH-domain-containing tyrosine kinase Etk by focal the focal adhesion kinase and cell adhesion kinase beta. J
adhesion kinase through the FERM domain. Nat Cell Biol Biol Chem 272, 25319-25325 (1997)
3, 439-444 (2001) 496. Klingbeil, C. K., C. R. Hauck, D. A. Hsia, K. C.
483. Hildebrand, J. D., M. D. Schaller, & J. T. Parsons. Jones, S. R. Reider, & D. D. Schlaepfer. Targeting Pyk2 to
Paxillin, a tyrosine phosphorylated focal adhesion- beta 1-integrin-containing focal contacts rescues
associated protein binds to the carboxyl terminal domain of fibronectin-stimulated signaling and haptotactic motility

628
Non-receptor protein tyrosine kinases

defects of focal adhesion kinase-null cells. J Cell Biol 152, FAK in nerve growth factor-induced neuronal
97-110 (2001) differentiation. J Biol Chem 275, 19768-19777 (2000)
497. Du, Q. S., X. R. Ren, Y. Xie, Q. Wang, L. Mei, & W. 513. Huang, Y., W. Lu, D. W. Ali, K. A. Pelkey, G. M.
C. Xiong. Inhibition of PYK2-induced actin cytoskeleton Pitcher, Y. M. Lu, H. Aoto, J. C. Roder, T. Sasaki, M. W.
reorganization, PYK2 autophosphorylation and focal Salter, & J. F. MacDonald. CAKbeta/Pyk2 kinase is a
adhesion targeting by FAK. J Cell Sci 114, 2977-2987 signaling link for induction of long-term potentiation in
(2001) CA1 hippocampus. Neuron 29, 485-496 (2001)
498. Parsons, J. T., K. H. Martin, J. K. Slack, J. M. Taylor, 514. Ueki, K., T. Mimura, T. Nakamoto, T. Sasaki, S.
& S. A. Weed. Focal adhesion kinase: a regulator of focal Aizawa, H. Hirai, S. Yano, T. Naruse, & Y. Nojima.
adhesion dynamics and cell movement. Oncogene 19, Integrin-mediated signal transduction in cells lacking focal
5606-5613 (2000) adhesion kinase p125FAK. FEBS Lett 432, 197-201 (1998)
499. Schaller, M. D. Biochemical signals and biological 515. Sieg, D. J., D. Ilic, K. C. Jones, C. H. Damsky, T.
responses elicited by the focal adhesion kinase. Biochim Hunter, & D. D. Schlaepfer. Pyk2 and Src-family protein-
Biophys Acta 1540, 1-21 (2001) tyrosine kinases compensate for the loss of FAK in
500. Turner, C. E. Paxillin and focal adhesion signalling. fibronectin-stimulated signaling events but Pyk2 does not
Nat Cell Biol 2, E231-236 (2000) fully function to enhance FAK- cell migration. Embo J 17,
501. Ilic, D., Y. Furuta, S. Kanazawa, N. Takeda, K. 5933-5947 (1998)
Sobue, N. Nakatsuji, S. Nomura, J. Fujimoto, M. Okada, & 516. Furuta, Y., D. Ilic, S. Kanazawa, N. Takeda, T.
T. Yamamoto. Reduced cell motility and enhanced focal Yamamoto, & S. Aizawa. Mesodermal defect in late phase
adhesion contact formation in cells from FAK-deficient of gastrulation by a targeted mutation of focal adhesion
mice. Nature 377, 539-544 (1995) kinase, FAK. Oncogene 11, 1989-1995 (1995)
502. Fincham, V. J., J. A. Wyke, & M. C. Frame. v-Src- 517. Ilic, D., S. Kanazawa, Y. Furuta, T. Yamamoto, & S.
induced degradation of focal adhesion kinase during Aizawa. Impairment of mobility in endodermal cells by
morphological transformation of chicken embryo FAK deficiency. Exp Cell Res 222, 298-303 (1996)
fibroblasts. Oncogene 10, 2247-2252 (1995) 518. Guinamard, R., M. Okigaki, J. Schlessinger, & J. V.
503. Ren, X. D., W. B. Kiosses, D. J. Sieg, C. A. Otey, D. Ravetch. Absence of marginal zone B cells in Pyk-2-
D. Schlaepfer, & M. A. Schwartz. Focal adhesion kinase deficient mice defines their role in the humoral response.
suppresses Rho activity to promote focal adhesion turnover. Nat Immunol 1, 31-36 (2000)
J Cell Sci 113, 3673-3678 (2000) 519. Chan, P. Y., S. B. Kanner, G. Whitney, & A. Aruffo.
504. Zhao, J. H., H. Reiske, & J. L. Guan. Regulation of A transmembrane-anchored chimeric focal adhesion kinase
the cell cycle by focal adhesion kinase. J Cell Biol 143, is constitutively activated and phosphorylated at tyrosine
1997-2008 (1998) residues identical to pp125FAK. Journal of Biological
505. Frisch, S. M., K. Vuori, E. Ruoslahti, & P. Y. Chan- Chemistry 269, 20567-20574 (1994)
Hui. Control of adhesion-dependent cell survival by focal 520. Calalb, M. B., T. R. Polte, & S. K. Hanks. Tyrosine
adhesion kinase. Journal of Cell Biology 134, 793-799 phosphorylation of focal adhesion kinase at sites in the
(1996) catalytic domain regulates kinase activity: a role for Src
506. Sonoda, Y., Y. Matsumoto, M. Funakoshi, D. family kinases. Molecular & Cellular Biology 15, 954-963
Yamamoto, S. K. Hanks, & T. Kasahara. Anti-apoptotic (1995)
role of focal adhesion kinase (FAK). Induction of inhibitor- 521. Zhang, X., A. Chattopadhyay, Q. S. Ji, J. D. Owen, P.
of-apoptosis proteins and apoptosis suppression by the J. Ruest, G. Carpenter, & S. K. Hanks. Focal adhesion
overexpression of FAK in a human leukemic cell line, HL- kinase promotes phospholipase C-gamma1 activity. Proc
60. J Biol Chem 275, 16309-16315 (2000) Natl Acad Sci U S A 96, 9021-9026 (1999)
507. Almeida, E. A., D. Ilic, Q. Han, C. R. Hauck, F. Jin, 522. Han, D. C., & J. L. Guan. Association of focal
H. Kawakatsu, D. D. Schlaepfer, & C. H. Damsky. Matrix adhesion kinase with Grb7 and its role in cell migration. J
survival signaling: from fibronectin via focal adhesion Biol Chem 274, 24425-24430 (1999)
kinase to c-Jun NH(2)-terminal kinase. J Cell Biol 149, 523. Reiske, H. R., S. C. Kao, L. A. Cary, J. L. Guan, J. F.
741-754 (2000) Lai, & H. C. Chen. Requirement of phosphatidylinositol 3-
508. Girault, J. A., A. Costa, P. Derkinderen, J. M. Studler, kinase in focal adhesion kinase-promoted cell migration. J
& M. Toutant. FAK and PYK2/CAKbeta in the nervous Biol Chem 274, 12361-12366 (1999)
system: a link between neuronal activity, plasticity and 524. Schlaepfer, D. D., S. K. Hanks, T. Hunter, & P. van
survival? Trends Neurosci 22, 257-263 (1999) der Geer. Integrin-mediated signal transduction linked to
509. Avraham, H., S. Y. Park, K. Schinkmann, & S. Ras pathway by GRB2 binding to focal adhesion kinase.
Avraham. RAFTK/Pyk2-mediated cellular signalling. Cell Nature 372, 786-791 (1994)
Signal 12, 123-133 (2000) 525. Schlaepfer, D. D., & T. Hunter. Evidence for in vivo
510. Shi, C. S., & J. H. Kehrl. PYK2 links G(q)alpha and phosphorylation of the Grb2 SH2-domain binding site on
G(13)alpha signaling to NF-kappa B activation. J Biol focal adhesion kinase by Src-family protein-tyrosine
Chem 276, 31845-31850 (2001) kinases. Molecular & Cellular Biology 16, 5623-5633
511. Zhao, J., C. Zheng, & J. Guan. Pyk2 and FAK (1996)
differentially regulate progression of the cell cycle. J Cell 526. Nakamura, K., H. Yano, E. Schaefer, & H. Sabe.
Sci 113, 3063-3072 (2000) Different modes and qualities of tyrosine phosphorylation
512. Park, S. Y., H. Avraham, & S. Avraham. of Fak and Pyk2 during epithelial-mesenchymal
Characterization of the tyrosine kinases RAFTK/Pyk2 and transdifferentiation and cell migration: analysis of specific

629
Non-receptor protein tyrosine kinases

phosphorylation events using site-directed antibodies. 540. Kruh, G. D., R. Perego, T. Miki, & S. A. Aaronson.
Oncogene 20, 2626-2635 (2001) The complete coding sequence of arg defines the Abelson
527. Li, X., R. C. Dy, W. G. Cance, L. M. Graves, & H. S. subfamily of cytoplasmic tyrosine kinases. Proceedings of
Earp. Interactions between two cytoskeleton-associated the National Academy of Sciences of the United States of
tyrosine kinases: calcium-dependent tyrosine kinase and America 87, 5802-5806 (1990)
focal adhesion tyrosine kinase. J Biol Chem 274, 8917- 541. Perego, R., D. Ron, & G. D. Kruh. Arg encodes a
8924 (1999) widely expressed 145 kDa protein-tyrosine kinase.
528. Ma, A., A. Richardson, E. M. Schaefer, & J. T. Oncogene 6, 1899-1902 (1991)
Parsons. Serine phosphorylation of focal adhesion kinase in 542. Tybulewicz, V. L., C. E. Crawford, P. K. Jackson, R.
interphase and mitosis: a possible role in modulating T. Bronson, & R. C. Mulligan. Neonatal lethality and
binding to p130(Cas). Mol Biol Cell 12, 1-12 (2001) lymphopenia in mice with a homozygous disruption of the
529. Rodriguez-Fernandez, J. L., L. Sanchez-Martin, M. c-abl proto-oncogene. Cell 65, 1153-1163 (1991)
Rey, M. Vicente-Manzanares, S. Narumiya, J. Teixido, F. 543. Robinson, D., F. He, T. Pretlow, & H. J. Kung. A
Sanchez-Madrid, & C. Cabanas. Rho and Rho-associated tyrosine kinase profile of prostate carcinoma. Proc Natl
kinase modulate the tyrosine kinase PYK2 in T- cells Acad Sci U S A 93, 5958-5962 (1996)
through regulation of the activity of the integrin LFA-1. J 544. Koleske, A. J., A. M. Gifford, M. L. Scott, M. Nee, R.
Biol Chem 276, 40518-40527 (2001) T. Bronson, K. A. Miczek, & D. Baltimore. Essential roles
530. Tang, H., Z. J. Zhao, E. J. Landon, & T. Inagami. for the Abl and Arg tyrosine kinases in neurulation. Neuron
Regulation of calcium-sensitive tyrosine kinase Pyk2 by 21, 1259-1272 (1998)
angiotensin II in endothelial cells. Roles of Yes tyrosine 545. Chen, W. S., H. J. Kung, W. K. Yang, & W. Lin.
kinase and tyrosine phosphatase SHP-2. J Biol Chem 275, Comparative tyrosine-kinase profiles in colorectal cancers:
8389-8396 (2000) enhanced arg expression in carcinoma as compared with
531. Lyons, P. D., J. M. Dunty, E. M. Schaefer, & M. D. adenoma and normal mucosa. Int J Cancer 83, 579-584
Schaller. Inhibition of the catalytic activity of cell adhesion (1999)
kinase beta by protein-tyrosine phosphatase-PEST- 546. Raitano, A. B., Y. E. Whang, & C. L. Sawyers. Signal
mediated dephosphorylation. J Biol Chem 276, 24422- transduction by wild-type and leukemogenic Abl proteins.
24431 (2001) Biochim Biophys Acta 1333, F201-216 (1997)
532. Ueda, H., S. Abbi, C. Zheng, & J. L. Guan. 547. Shaul, Y. c-Abl: activation and nuclear targets. Cell
Suppression of Pyk2 kinase and cellular activities by Death Differ 7, 10-16 (2000)
FIP200. J Cell Biol 149, 423-430 (2000) 548. Smith, J. M., & B. J. Mayer. Abl: mechanisms of
533. Schaller, M. D., C. A. Borgman, & J. T. Parsons. regulation and activation. Front Biosci 7, d31-42 (2002)
Autonomous expression of a noncatalytic domain of the 549. Wang, B., T. Mysliwiec, D. Krainc, R. A. Jensen, G.
focal adhesion-associated protein tyrosine kinase Sonoda, J. R. Testa, E. A. Golemis, & G. D. Kruh.
pp125FAK. Molecular & Cellular Biology 13, 785-791 Identification of ArgBP1, an Arg protein tyrosine kinase
(1993) binding protein that is the human homologue of a CNS-
534. Nolan, K., J. Lacoste, & J. T. Parsons. Regulated specific Xenopus gene. Oncogene 12, 1921-1929 (1996)
expression of focal adhesion kinase-related nonkinase, the 550. Wang, Y., A. L. Miller, M. S. Mooseker, & A. J.
autonomously expressed C-terminal domain of focal Koleske. The Abl-related gene (Arg) nonreceptor tyrosine
adhesion kinase. Mol Cell Biol 19, 6120-6129 (1999) kinase uses two F-actin-binding domains to bundle F-actin.
535. Richardson, A., & T. Parsons. A mechanism for Proc Natl Acad Sci U S A 98, 14865-14870 (2001)
regulation of the adhesion-associated proteintyrosine kinase 551. Van Etten, R. A. Cycling, stressed-out and nervous:
pp125FAK. Nature 380, 538-540 (1996) cellular functions of c-Abl. Trends Cell Biol 9, 179-186
536. Xu, L. H., X. Yang, C. A. Bradham, D. A. Brenner, (1999)
A. S. Baldwin, Jr., R. J. Craven, & W. G. Cance. The focal 552. Van Etten, R. A., P. Jackson, & D. Baltimore. The
adhesion kinase suppresses transformation-associated, mouse type IV c-abl gene product is a nuclear protein, and
anchorage-independent apoptosis in human breast cancer activation of transforming ability is associated with
cells. Involvement of death receptor-related signaling cytoplasmic localization. Cell 58, 669-678 (1989)
pathways. J Biol Chem 275, 30597-30604 (2000) 553. Gertler, F. B., R. L. Bennett, M. J. Clark, & F. M.
537. Taylor, J. M., C. P. Mack, K. Nolan, C. P. Regan, G. Hoffmann. Drosophila abl tyrosine kinase in embryonic
K. Owens, & J. T. Parsons. Selective expression of an CNS axons: a role in axonogenesis is revealed through
endogenous inhibitor of FAK regulates proliferation and dosage-sensitive interactions with disabled. Cell 58, 103-
migration of vascular smooth muscle cells. Mol Cell Biol 113 (1989)
21, 1565-1572 (2001) 554. Wetzler, M., M. Talpaz, R. A. Van Etten, C. Hirsh-
538. Muller, R., D. J. Slamon, J. M. Tremblay, M. J. Cline, Ginsberg, M. Beran, & R. Kurzrock. Subcellular
& I. M. Verma. Differential expression of cellular localization of Bcr, Abl, and Bcr-Abl proteins in normal
oncogenes during pre- and postnatal development of the and leukemic cells and correlation of expression with
mouse. Nature 299, 640-644 (1982) myeloid differentiation. J Clin Invest 92, 1925-1939 (1993)
539. Renshaw, M. W., M. A. Capozza, & J. Y. Wang. 555. Wang, B., & G. D. Kruh. Subcellular localization of the
Differential expression of type-specific c-abl mRNAs in Arg protein tyrosine kinase. Oncogene 13, 193-197 (1996)
mouse tissues and cell lines. Mol Cell Biol 8, 4547-4551 556. Wen, S. T., P. K. Jackson, & R. A. Van Etten. The
(1988) cytostatic function of c-Abl is controlled by multiple
nuclear localization signals and requires the p53 and Rb

630
Non-receptor protein tyrosine kinases

tumor suppressor gene products. Embo J 15, 1583-1595 kinase in response to ionizing radiation. Nature 387, 516-
(1996) 519 (1997)
557. Taagepera, S., D. McDonald, J. E. Loeb, L. L. 570. Sawyers, C. L., J. Mclaughlin, A. Goga, M. Havlik, &
Whitaker, A. K. McElroy, J. Y. Wang, & T. J. Hope. O. Witte. The nuclear tyrosine kinase C-ABL negatively
Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase. regulates cell growth. Cell 77, 121-131 (1994)
Proc Natl Acad Sci U S A 95, 7457-7462 (1998) 571. Yuan, Z. M., Y. Huang, Y. Whang, C. Sawyers, R.
558. Franz, W. M., P. Berger, & J. Y. Wang. Deletion of Weichselbaum, S. Kharbanda, & D. Kufe. Role for c-Abl
an N-terminal regulatory domain of the c-abl tyrosine tyrosine kinase in growth arrest response to DNA damage.
kinase activates its oncogenic potential. EMBO Journal 8, Nature 382, 272-274 (1996)
137-147 (1989) 572. Yuan, Z. M., Y. Huang, M. M. Fan, C. Sawyers, S.
559. Daley, G. Q., R. A. Van Etten, P. K. Jackson, A. Kharbanda, & D. Kufe. Genotoxic drugs induce interaction
Bernards, & D. Baltimore. Nonmyristoylated Abl proteins of the c-Abl tyrosine kinase and the tumor suppressor
transform a factor-dependent hematopoietic cell line. protein p53. Journal of Biological Chemistry 271, 26457-
Molecular & Cellular Biology 12, 1864-1871 (1992) 26460 (1996)
560. McWhirter, J. R., & J. Y. Wang. Activation of 573. Agami, R., G. Blandino, M. Oren, & Y. Shaul.
tyrosinase kinase and microfilament-binding functions of c- Interaction of c-Abl and p73alpha and their collaboration to
abl by bcr sequences in bcr/abl fusion proteins. Molecular induce apoptosis. Nature 399, 809-813 (1999)
& Cellular Biology 11, 1553-1565 (1991) 574. Yuan, Z. M., H. Shioya, T. Ishiko, X. Sun, J. Gu, Y.
561. Van Etten, R. A., P. K. Jackson, D. Baltimore, M. C. Y. Huang, H. Lu, S. Kharbanda, R. Weichselbaum, & D.
Sanders, P. T. Matsudaira, & P. A. Janmey. The COOH Kufe. p73 is regulated by tyrosine kinase c-Abl in the
terminus of the c-Abl tyrosine kinase contains distinct F- apoptotic response to DNA damage. Nature 399, 814-817
and G-actin binding domains with bundling activity. (1999)
Journal of Cell Biology 124, 325-340 (1994) 575. Yuan, Z. M., Y. Huang, T. Ishiko, S. Kharbanda, R.
562. Lewis, J. M., R. Baskaran, S. Taagepera, M. A. Weichselbaum, & D. Kufe. Regulation of DNA damage-
Schwartz, & J. Y. Wang. Integrin regulation of c-Abl induced apoptosis by the c-Abl tyrosine kinase.
tyrosine kinase activity and cytoplasmic-nuclear transport. Proceedings of the National Academy of Sciences of the
Proceedings of the National Academy of Sciences of the United States of America 94, 1437-1440 (1997)
United States of America 93, 15174-15179 (1996) 576. Dorsch, M., & S. P. Goff. Increased sensitivity to
563. Baskaran, R., M. E. Dahmus, & J. Y. J. Wang. apoptotic stimuli in c-abl-deficient progenitor B-cell lines.
Tyrosine phosphorylation of mammalian RNA polymerase- Proc Natl Acad Sci U S A 93, 13131-13136 (1996)
II carboxyl-terminal domain. Proc Natl Acad Sci USA 90, 577. Baskaran, R., G. G. Chiang, T. Mysliwiec, G. D.
11167-11171 (1993) Kruh, & J. Y. Wang. Tyrosine phosphorylation of RNA
564. Duyster, J., R. Baskaran, & J. Y. Wang. Src polymerase II carboxyl-terminal domain by the Abl-related
homology 2 domain as a specificity determinant in the c- gene product. J Biol Chem 272, 18905-18909 (1997)
Abl-mediated tyrosine phosphorylation of the RNA 578. Lewis, J. M., & M. A. Schwartz. Integrins regulate
polymerase II carboxyl-terminal repeated domain. the association and phosphorylation of paxillin by c- Abl. J
Proceedings of the National Academy of Sciences of the Biol Chem 273, 14225-14230 (1998)
United States of America 92, 1555-1559 (1995) 579. Feller, S. M., B. Knudsen, & H. Hanafusa. c-Abl
565. Goga, A., X. Liu, T. M. Hambuch, K. Senechal, E. kinase regulates the protein binding activity of c-Crk.
Major, A. J. Berk, O. N. Witte, & C. L. Sawyers. p53 EMBO J 13, 2341-2351 (1994)
dependent growth suppression by the c-Abl nuclear 580. Yano, H., F. Cong, R. B. Birge, S. P. Goff, & M. V.
tyrosine kinase. Oncogene 11, 791-799 (1995) Chao. Association of the Abl tyrosine kinase with the Trk
566. Kharbanda, S., P. Pandey, S. Jin, S. Inoue, A. Bharti, nerve growth factor receptor. J Neurosci Res 59, 356-364
Z. M. Yuan, R. Weichselbaum, D. Weaver, & D. Kufe. (2000)
Functional interaction between DNA-PK and c-Abl in 581. Kain, K. H., & R. L. Klemke. Inhibition of cell
response to DNA damage. Nature 386, 732-735 (1997) migration by Abl family tyrosine kinases through
567. Nehme, A., R. Baskaran, S. Aebi, D. Fink, S. Nebel, uncoupling of Crk-CAS complexes. J Biol Chem 276,
B. Cenni, J. Y. J. Wang, S. B. Howell, & R. D. Christen. 16185-16192 (2001)
Differential induction of C-Jun NH2-terminal kinase and 582. Lu, Q., N. K. Mukhopadhyay, J. D. Griffin, M.
C-Abl Kinase in DNA mismatch repair-proficient and Paredes, M. Medina, & K. S. Kosik. Brain armadillo
deficient cells exposed to Cisplatin. Cancer Research 57, protein delta-catenin interacts with Abl tyrosine kinase and
3253-3257 (1997) modulates cellular morphogenesis in response to growth
568. Shafman, T., K. K. Khanna, P. Kedar, K. Spring, S. factors. J Neurosci Res 67, 618-624 (2002)
Kozlov, T. Yen, K. Hobson, M. Gatei, N. Zhang, D. 583. Plattner, R., L. Kadlec, K. A. DeMali, A.
Watters, M. Egerton, Y. Shiloh, S. Kharbanda, D. Kufe, & Kazlauskas, & A. M. Pendergast. c-Abl is activated by
M. F. Lavin. Interaction between ATM protein and c-Abl in growth factors and Src family kinases and has a role in
response to DNA damage [see comments]. Nature 387, the cellular response to PDGF. Genes Dev 13, 2400-
520-523 (1997) 2411 (1999)
569. Baskaran, R., L. D. Wood, L. L. Whitaker, C. E. 584. Yu, H. H., A. H. Zisch, V. C. Dodelet, & E. B.
Canman, S. E. Morgan, Y. Xu, C. Barlow, D. Baltimore, A. Pasquale. Multiple signaling interactions of Abl and Arg
Wynshaw-Boris, M. B. Kastan, & J. Y. Wang. Ataxia kinases with the EphB2 receptor. Oncogene 20, 3995-4006
telangiectasia mutant protein activates c-Abl tyrosine (2001)

631
Non-receptor protein tyrosine kinases

585. Schwartzberg, P. L., A. M. Stall, J. D. Hardin, K. S. leukemic myeloid cells. Proc Natl Acad Sci U S A 82,
Bowdish, T. Humaran, S. Boast, M. L. Harbison, E. J. 2379-2383 (1985)
Robertson, & S. P. Goff. Mice homozygous for the ablm1 601. MacDonald, I., J. Levy, & T. Pawson. Expression of
mutation show poor viability and depletion of selected B the mammalian c-fes protein in hematopoietic cells and
and T cell populations. Cell 65, 1165-1175 (1991) identification of a distinct fes-related protein. Mol Cell Biol
586. Jackson, P., & D. Baltimore. N-terminal mutations 5, 2543-2551 (1985)
activate the leukemogenic potential of the myristoylated 602. Care, A., G. Mattia, E. Montesoro, I. Parolini, G.
form of c-abl. EMBO Journal 8, 449-456 (1989) Russo, M. P. Colombo, & C. Peschle. C-Fes expression in
587. Mayer, B. J., & D. Baltimore. Mutagenic analysis of ontogenetic development and hematopoietic differentiation.
the roles of SH2 and SH3 domains in regulation of the Abl Oncogene 9, 739-747 (1994)
tyrosine kinase. Molecular & Cellular Biology 14, 2883- 603. Greer, P., J. Haigh, G. Mbamalu, W. Khoo, A.
2894 (1994) Bernstein, & T. Pawson. The Fps/Fes protein-tyrosine
588. Van Etten, R. A., J. Debnath, H. Zhou, & J. M. kinase promotes angiogenesis in transgenic mice. Mol Cell
Casasnovas. Introduction of a loss-of-function point Biol 14, 6755-6763 (1994)
mutation from the SH3 region of the Caenorhabditis 604. Haigh, J., J. McVeigh, & P. Greer. The fps/fes
elegans sem-5 gene activates the transforming ability of c- tyrosine kinase is expressed in myeloid, vascular
abl in vivo and abolishes binding of proline-rich ligands in endothelial, epithelial, and neuronal cells and is localized in
vitro. Oncogene 10, 1977-1988 (1995) the trans-golgi network. Cell Growth Differ 7, 931-944
589. Cicchetti, P., B. J. Mayer, G. Thiel, & D. Baltimore. (1996)
Identification of a protein that binds to the SH3 region of 605. Letwin, K., S. P. Yee, & T. Pawson. Novel protein-
Abl and is similar to Bcr and GAP-rho. Science 257, 803- tyrosine kinase cDNAs related to fps/fes and eph cloned
806 (1992) using anti-phosphotyrosine antibody. Oncogene 3, 621-627
590. Ren, R., B. J. Mayer, P. Cicchetti, & D. Baltimore. (1988)
Identification of a ten-amino acid proline-rich SH3 binding 606. Young, J. C., & G. S. Martin. Cellular localization of
site. Science 259, 1157-1161 (1993) c-fps gene product NCP98. J Virol 52, 913-918 (1984)
591. Shi, Y., K. Alin, & S. P. Goff. Abl-interactor-1, a 607. Zirngibl, R., D. Schulze, S. E. Mirski, S. P. Cole, &
novel SH3 protein binding to the carboxy-terminal portion P. A. Greer. Subcellular localization analysis of the closely
of the Abl protein, suppresses v-abl transforming activity. related Fps/Fes and Fer protein-tyrosine kinases suggests a
Genes & Development 9, 2583-2597 (1995) distinct role for Fps/Fes in vesicular trafficking. Exp Cell
592. Dai, Z., & A. M. Pendergast. Abi-2, a novel SH3- Res 266, 87-94 (2001)
containing protein interacts with the c-Abl tyrosine kinase 608. Jucker, M., K. McKenna, A. J. da Silva, C. E. Rudd,
and modulates c-Abl transforming activity. Genes & & R. A. Feldman. The Fes protein-tyrosine kinase
Development 9, 2569-2582 (1995) phosphorylates a subset of macrophage proteins that are
593. Zhu, J., & S. K. Shore. c-ABL tyrosine kinase activity involved in cell adhesion and cell-cell signaling. Journal of
is regulated by association with a novel SH3-domain- Biological Chemistry 272, 2104-2109 (1997)
binding protein. Molecular & Cellular Biology 16, 7054- 609. Hao, Q. L., D. K. Ferris, G. White, N. Heisterkamp,
7062 (1996) & J. Groffen. Nuclear and cytoplasmic location of the FER
594. Wen, S. T., & R. A. Van Etten. The PAG gene tyrosine kinase. Mol Cell Biol 11, 1180-1183 (1991)
product, a stress-induced protein with antioxidant 610. Yates, K. E., M. R. Lynch, S. G. Wong, D. J. Slamon,
properties, is an Abl SH3-binding protein and a & J. C. Gasson. Human c-FES is a nuclear tyrosine kinase.
physiological inhibitor of c-Abl tyrosine kinase activity. Oncogene 10, 1239-1242 (1995)
Genes Dev 11, 2456-2467 (1997) 611. Hanazono, Y., S. Chiba, K. Sasaki, H. Mano, A.
595. Brasher, B. B., & R. A. Van Etten. c-Abl has high Miyajima, K. Arai, Y. Yazaki, & H. Hirai. c-Fps/Fes
intrinsic tyrosine kinase activity that is stimulated by protein-tyrosine kinase is implicated in a signaling pathway
mutation of the Src homology 3 domain and by triggered by granulocyte-macrophage colony-stimulating
autophosphorylation at two distinct regulatory tyrosines. J factor and interleukin-3. EMBO J 12, 1641-1646 (1993)
Biol Chem 275, 35631-35637 (2000) 612. Hanazono, Y., S. Chiba, K. Sasaki, H. Mano, Y.
596. Pluk, H., K. Dorey, & G. Superti-Furga. Yazaki, & H. Hirai. Erythropoietin induces tyrosine
Autoinhibition of c-Abl. Cell 108, 247-259 (2002) phosphorylation and kinase activity of the c-fps/fes proto-
597. Brasher, B. B., S. Roumiantsev, & R. A. Van Etten. oncogene product in human erythropoietin-responsive cells.
Mutational analysis of the regulatory function of the c-Abl Blood 81, 3193-3196 (1993)
Src homology 3 domain. Oncogene 20, 7744-7752 (2001) 613. Izuhara, K., R. A. Feldman, P. Greer, & N. Harada.
598. Smithgall, T. E., J. A. Rogers, K. L. Peters, J. Li, S. Interaction of the c-fes proto-oncogene product with the
D. Briggs, J. M. Lionberger, H. Cheng, A. Shibata, B. interleukin-4 receptor. J Biol Chem 269, 18623-18629 (1994)
Scholtz, S. Schreiner, & N. Dunham. The c-Fes family of 614. Matsuda, T., T. Fukada, M. Takahashi-Tezuka, Y.
protein-tyrosine kinases. Crit Rev Oncog 9, 43-62 (1998) Okuyama, Y. Fujitani, Y. Hanazono, H. Hirai, & T. Hirano.
599. Greer, P. Closing in on the biological functions of Activation of Fes tyrosine kinase by gp130, an interleukin-
Fps/Fes and Fer. Nat Rev Mol Cell Biol 3, 278-289 (2002) 6 family cytokine signal transducer, and their association. J
600. Feldman, R. A., J. L. Gabrilove, J. P. Tam, M. A. Biol Chem 270, 11037-11039 (1995)
Moore, & H. Hanafusa. Specific expression of the human 615. Izuhara, K., R. A. Feldman, P. Greer, & N. Harada.
cellular fps/fes-encoded protein NCP92 in normal and Interleukin-4 induces association of the c-fes proto-

632
Non-receptor protein tyrosine kinases

oncogene product with phosphatidylinositol-3 kinase. protein tyrosine kinase (p93c-fes) by its src homology 2
Blood 88, 3910-3918 (1996) domain and major autophosphorylation site (Tyr-713).
616. Brizzi, M. F., M. G. Aronica, A. Rosso, G. P. Oncogene 8, 2283-2292 (1993)
Bagnara, Y. Yarden, & L. Pegoraro. Granulocyte- 631. Fang, F., S. Ahmad, J. Lei, R. W. Klecker, J. B.
macrophage colony-stimulating factor stimulates JAK2 Trepel, T. E. Smithgall, & R. I. Glazer. Effect of the
signaling pathway and rapidly activates p93fes, STAT1 mutation of tyrosine 713 in p93c-fes on its catalytic activity
p91, and STAT3 p92 in polymorphonuclear leukocytes. J and ability to promote myeloid differentiation in K562
Biol Chem 271, 3562-3567 (1996) cells. Biochemistry 32, 6995-7001 (1993)
617. Senis, Y., R. Zirngibl, J. McVeigh, A. Haman, T. 632. Rogers, J. A., R. D. Read, J. Li, K. L. Peters, & T. E.
Hoang, & P. A. Greer. Targeted disruption of the murine Smithgall. Autophosphorylation of the Fes tyrosine kinase.
fps/fes proto-oncogene reveals that Fps/Fes kinase activity Evidence for an intermolecular mechanism involving two
is dispensable for hematopoiesis. Mol Cell Biol 19, 7436- kinase domain tyrosine residues. Journal of Biological
7446 (1999) Chemistry 271, 17519-17525 (1996)
618. Hackenmiller, R., J. Kim, R. A. Feldman, & M. C. 633. Ben-Dor, I., O. Bern, T. Tennenbaum, & U. Nir. Cell
Simon. Abnormal Stat activation, hematopoietic cycle-dependent nuclear accumulation of the p94fer
homeostasis, and innate immunity in c-fes-/- mice. tyrosine kinase is regulated by its NH2 terminus and is
Immunity 13, 397-407 (2000) affected by kinase domain integrity and ATP binding. Cell
619. Zirngibl, R. A., Y. Senis, & P. A. Greer. Enhanced Growth Differ 10, 113-129 (1999)
endotoxin sensitivity in fps/fes-null mice with minimal 634. Craig, A. W., R. Zirngibl, & P. Greer. Disruption of
defects in hematopoietic homeostasis. Mol Cell Biol 22, coiled-coil domains in Fer protein-tyrosine kinase abolishes
2472-2486 (2002) trimerization but not kinase activation. J Biol Chem 274,
620. Hackenmiller, R., & M. C. Simon. Truncation of c-fes 19934-19942 (1999)
via gene targeting results in embryonic lethality and 635. Rogers, J. A., H. Y. Cheng, & T. E. Smithgall. Src
hyperproliferation of hematopoietic cells. Dev Biol 245, homology 2 domain substitution modulates the kinase and
255-269 (2002) transforming activities of the Fes protein-tyrosine kinase.
621. Craig, A. W., R. Zirngibl, K. Williams, L. A. Cole, & Cell Growth Differ 11, 581-592 (2000)
P. A. Greer. Mice devoid of fer protein-tyrosine kinase 636. Read, R. D., J. M. Lionberger, & T. E. Smithgall.
activity are viable and fertile but display reduced cortactin Oligomerization of the Fes tyrosine kinase. Evidence for a
phosphorylation. Mol Cell Biol 21, 603-613 (2001) coiled-coil domain in the unique N-terminal region. J Biol
622. Kim, L., & T. W. Wong. The cytoplasmic tyrosine Chem 272, 18498-18503 (1997)
kinase FER is associated with the catenin-like substrate 637. Cheng, H. Y., A. P. Schiavone, & T. E. Smithgall. A
pp120 and is activated by growth factors. Mol Cell Biol 15, point mutation in the N-terminal coiled-coil domain
4553-4561 (1995) releases c-Fes tyrosine kinase activity and survival
623. Kim, L., & T. W. Wong. Growth factor-dependent signaling in myeloid leukemia cells. Mol Cell Biol 21,
phosphorylation of the actin-binding protein cortactin is 6170-6180 (2001)
mediated by the cytoplasmic tyrosine kinase FER. J Biol 638. Lee, J., Z. Wang, S. M. Luoh, W. I. Wood, & D. T.
Chem 273, 23542-23548 (1998) Scadden. Cloning of FRK, a novel human intracellular
624. Li, H., T. C. Leung, S. Hoffman, J. Balsamo, & J. SRC-like tyrosine kinase- encoding gene. Gene 138, 247-
Lilien. Coordinate regulation of cadherin and integrin 251 (1994)
function by the chondroitin sulfate proteoglycan neurocan. 639. Cance, W. G., R. J. Craven, M. Bergman, L. Xu, K.
J Cell Biol 149, 1275-1288 (2000) Alitalo, & E. T. Liu. Rak, a novel nuclear tyrosine kinase
625. Arregui, C., P. Pathre, J. Lilien, & J. Balsamo. The expressed in epithelial cells. Cell Growth & Differentiation
nonreceptor tyrosine kinase fer mediates cross-talk between 5, 1347-1355 (1994)
N-cadherin and beta1-integrins. J Cell Biol 149, 1263-1274 640. Oberg-Welsh, C., & M. Welsh. Cloning of BSK, a
(2000) murine FRK homologue with a specific pattern of tissue
626. Rosato, R., J. M. Veltmaat, J. Groffen, & N. distribution. Gene 152, 239-242 (1995)
Heisterkamp. Involvement of the tyrosine kinase fer in cell 641. Thuveson, M., D. Albrecht, G. Zurcher, A. C. Andres,
adhesion. Mol Cell Biol 18, 5762-5770 (1998) & A. Ziemiecki. Iyk, a novel intracellular protein tyrosine
627. McCafferty, D. M., A. W. Craig, Y. A. Senis, & P. A. kinase differentially expressed in the mouse mammary
Greer. Absence of Fer protein-tyrosine kinase exacerbates gland and intestine. Biochemical & Biophysical Research
leukocyte recruitment in response to endotoxin. J Immunol Communications 209, 582-589 (1995)
168, 4930-4935 (2002) 642. Sunitha, I., & M. I. Avigan. The apical membranes of
628. Craig, A. W., & P. A. Greer. Fer kinase is required maturing gut columnar epithelial cells contain the
for sustained p38 kinase activation and maximal enzymatically active form of a newly identified fyn-related
chemotaxis of activated mast cells. Mol Cell Biol 22, 6363- tyrosine kinase. Oncogene 13, 547-559 (1996)
6374 (2002) 643. Lee, S. T., K. M. Strunk, & R. A. Spritz. A survey of
629. Weinmaster, G., E. Hinze, & T. Pawson. Mapping of protein tyrosine kinase mRNAs expressed in normal human
multiple phosphorylation sites within the structural and melanocytes. Oncogene 8, 3403-3410 (1993)
catalytic domains of the Fujinami avian sarcoma virus 644. Mitchell, P. J., K. T. Barker, J. E. Martindale, T.
transforming protein. J Virol 46, 29-41 (1983) Kamalati, P. N. Lowe, M. J. Page, B. A. Gusterson, & M.
630. Hjermstad, S. J., K. L. Peters, S. D. Briggs, R. I. R. Crompton. Cloning and characterisation of cDNAs
Glazer, & T. E. Smithgall. Regulation of the human c-fes encoding a novel non-receptor tyrosine kinase, brk,

633
Non-receptor protein tyrosine kinases

expressed in human breast tumours. Oncogene 9, 2383- 659. Kamalati, T., H. E. Jolin, M. J. Fry, & M. R.
2390 (1994) Crompton. Expression of the BRK tyrosine kinase in
645. Vasioukhin, V., M. S. Serfas, E. Y. Siyanova, M. mammary epithelial cells enhances the coupling of EGF
Polonskaia, V. J. Costigan, B. Liu, A. Thomason, & A. L. signalling to PI 3-kinase and Akt, via erbB3
Tyner. A novel intracellular epithelial cell tyrosine kinase phosphorylation. Oncogene 19, 5471-5476 (2000)
is expressed in the skin and gastrointestinal tract. Oncogene 660. Qiu, H., & W. T. Miller. Regulation of the
10, 349-357 (1995) nonreceptor tyrosine kinase brk by autophosphorylation
646. Kohmura, N., T. Yagi, Y. Tomooka, M. Oyanagi, R. and by autoinhibition. J Biol Chem 277, 34634-34641
Kominami, N. Takeda, J. Chiba, Y. Ikawa, & S. Aizawa. A (2002)
novel nonreceptor tyrosine kinase, Srm: cloning and 661. Manser, E., T. Leung, H. Salihuddin, L. Tan, & L.
targeted disruption. Molecular & Cellular Biology 14, Lim. A non-receptor tyrosine kinase that inhibits the
6915-6925 (1994) GTPase activity of p21cdc42. Nature 363, 364-367 (1993)
647. Derry, J. J., S. Richard, H. Valderrama Carvajal, X. 662. Hoehn, G. T., T. Stokland, S. Amin, M. Ramirez, A.
Ye, V. Vasioukhin, A. W. Cochrane, T. Chen, & A. L. L. Hawkins, C. A. Griffin, D. Small, & C. I. Civin. Tnk1: a
Tyner. Sik (BRK) phosphorylates Sam68 in the nucleus novel intracellular tyrosine kinase gene isolated from
and negatively regulates its RNA binding ability. Mol Cell human umbilical cord blood CD34+/Lin-/CD38-
Biol 20, 6114-6126 (2000) stem/progenitor cells. Oncogene 12, 903-913 (1996)
648. Mitchell, P. J., K. T. Barker, J. Shipley, & M. R. 663. Yang, W., & R. A. Cerione. Cloning and
Crompton. Characterisation and chromosome mapping of characterization of a novel Cdc42-associated tyrosine
the human non receptor tyrosine kinase gene, brk. kinase, ACK-2, from bovine brain. J Biol Chem 272,
Oncogene 15, 1497-1502 (1997) 24819-24824 (1997)
649. Lee, H., M. Kim, K. H. Lee, K. N. Kang, & S. T. Lee. 664. Teo, M., L. Tan, L. Lim, & E. Manser. The tyrosine
Exon-intron structure of the human PTK6 gene kinase ACK1 associates with clathrin-coated vesicles
demonstrates that PTK6 constitutes a distinct family of through a binding motif shared by arrestin and other
non-receptor tyrosine kinase. Mol Cells 8, 401-407 (1998) adaptors. J Biol Chem 276, 18392-18398 (2001)
650. Siyanova, E. Y., M. S. Serfas, I. A. Mazo, & A. L. 665. Felschow, D. M., C. I. Civin, & G. T. Hoehn.
Tyner. Tyrosine kinase gene expression in the mouse small Characterization of the tyrosine kinase Tnk1 and its binding
intestine. Oncogene 9, 2053-2057 (1994) with phospholipase C-gamma1. Biochem Biophys Res
651. Llor, X., M. S. Serfas, W. Bie, V. Vasioukhin, M. Commun 273, 294-301 (2000)
Polonskaia, J. Derry, C. M. Abbott, & A. L. Tyner. 666. Yang, W., Q. Lin, J. L. Guan, & R. A. Cerione.
BRK/Sik expression in the gastrointestinal tract and in Activation of the Cdc42-associated tyrosine kinase-2
colon tumors. Clin Cancer Res 5, 1767-1777 (1999) (ACK-2) by cell adhesion via integrin beta1. J Biol Chem
652. Barker, K. T., L. E. Jackson, & M. R. Crompton. 274, 8524-8530 (1999)
BRK tyrosine kinase expression in a high proportion of 667. Eisenmann, K. M., J. B. McCarthy, M. A. Simpson,
human breast carcinomas. Oncogene 15, 799-805 (1997) P. J. Keely, J. L. Guan, K. Tachibana, L. Lim, E. Manser,
653. Craven, R. J., W. G. Cance, & E. T. Liu. The nuclear L. T. Furcht, & J. Iida. Melanoma chondroitin sulphate
tyrosine kinase Rak associates with the retinoblastoma proteoglycan regulates cell spreading through Cdc42, Ack-
protein pRb. Cancer Research 55, 3969-3972 (1995) 1 and p130cas. Nat Cell Biol 1, 507-513 (1999)
654. Oberg-Welsh, C., C. Anneren, & M. Welsh. Mutation 668. Bourdoulous, S., G. Orend, D. A. MacKenna, R.
of C-terminal tyrosine residues Y497/Y504 of the Src- Pasqualini, & E. Ruoslahti. Fibronectin matrix regulates
family member Bsk/Iyk decreases NIH3T3 cell activation of RHO and CDC42 GTPases and cell cycle
proliferation. Growth Factors 16, 111-124 (1998) progression. Journal of Cell Biology 143, 267-276 (1998)
655. Anneren, C., & M. Welsh. Role of the Bsk/Iyk non- 669. Satoh, T., J. Kato, K. Nishida, & Y. Kaziro. Tyrosine
receptor tyrosine kinase for the control of growth and phosphorylation of ACK in response to temperature shift-
hormone production in RINm5F cells. Growth Factors 17, down, hyperosmotic shock, and epidermal growth factor
233-247 (2000) stimulation. FEBS Letters 386, 230-234 (1996)
656. Anneren, C., K. A. Reedquist, J. L. Bos, & M. Welsh. 670. Kiyono, M., J. Kato, T. Kataoka, Y. Kaziro, & T.
GTK, a Src-related tyrosine kinase, induces nerve growth Satoh. Stimulation of Ras guanine nucleotide exchange
factor-independent neurite outgrowth in PC12 cells through activity of Ras-GRF1/CDC25(Mm) upon tyrosine
activation of the Rap1 pathway. Relationship to Shb phosphorylation by the Cdc42-regulated kinase ACK1. J
tyrosine phosphorylation and elevated levels of focal Biol Chem 275, 29788-29793 (2000)
adhesion kinase. J Biol Chem 275, 29153-29161 (2000) 671. Linseman, D. A., K. A. Heidenreich, & S. K. Fisher.
657. Chandrasekharan, S., T. H. Qiu, N. Alkharouf, K. Stimulation of M3 muscarinic receptors induces
Brantley, J. B. Mitchell, & E. T. Liu. Characterization of phosphorylation of the Cdc42 effector activated Cdc42Hs-
mice deficient in the Src family nonreceptor tyrosine kinase associated kinase-1 via a Fyn tyrosine kinase signaling
Frk/rak. Mol Cell Biol 22, 5235-5247 (2002) pathway. J Biol Chem 276, 5622-5628 (2001)
658. Kamalati, T., H. E. Jolin, P. J. Mitchell, K. T. Barker, L. E. 672. Kato-Stankiewicz, J., S. Ueda, T. Kataoka, Y. Kaziro,
Jackson, C. J. Dean, M. J. Page, B. A. Gusterson, & M. R. & T. Satoh. Epidermal growth factor stimulation of the
Crompton. Brk, a breast tumor-derived non-receptor protein- ACK1/Dbl pathway in a Cdc42 and Grb2-dependent
tyrosine kinase, sensitizes mammary epithelial cells to epidermal manner. Biochem Biophys Res Commun 284, 470-477
growth factor. J Biol Chem 271, 30956-30963 (1996) (2001)

634
 Non-receptor protein tyrosine kinases

673. Nur-e-Kamal, M. S., M. M. Qureshi, J. M. Kamal, W.

Montague, & H. Maruta. Construction of a cell-permeable
CDC42 binding fragment of ACK that inhibits v-Ha-Ras
transformation. Ann N Y Acad Sci 886, 285-288 (1999)
674. Yang, W., Q. Lin, J. Zhao, J. L. Guan, & R. A.
Cerione. The nonreceptor tyrosine kinase ACK2, a specific
target for Cdc42 and a negative regulator of cell growth and
focal adhesion complexes. J Biol Chem 276, 43987-43993
(2001)
675. Kato, J., Y. Kaziro, & T. Satoh. Activation of the
guanine nucleotide exchange factor Dbl following ACK1-
dependent tyrosine phosphorylation. Biochem Biophys Res
Commun 268, 141-147 (2000)
676. Worby, C. A., N. Simonson-Leff, J. C. Clemens, D.
Huddler, Jr., M. Muda, & J. E. Dixon. Drosophila Ack
targets its substrate, the sorting nexin DSH3PX1, to a
protein complex involved in axonal guidance. J Biol Chem
277, 9422-9428 (2002)
677. Yang, W., C. G. Lo, T. Dispenza, & R. A. Cerione.
The Cdc42 target ACK2 directly interacts with clathrin and
influences clathrin assembly. J Biol Chem 276, 17468-
17473 (2001)
678. Mott, H. R., D. Owen, D. Nietlispach, P. N. Lowe, E.
Manser, L. Lim, & E. D. Laue. Structure of the small G
protein Cdc42 bound to the GTPase-binding domain of
ACK. Nature 399, 384-388 (1999)
679. Morreale, A., M. Venkatesan, H. R. Mott, D. Owen,
D. Nietlispach, P. N. Lowe, & E. D. Laue. Structure of
Cdc42 bound to the GTPase binding domain of PAK. Nat
Struct Biol 7, 384-388 (2000)
680. Sem, K. P., B. Zahedi, I. Tan, M. Deak, L. Lim, & N.
Harden. ACK family tyrosine kinase activity is a
component of Dcdc42 signaling during dorsal closure in
Drosophila melanogaster. Mol Cell Biol 22, 3685-3697
(2002)

Key Words: Protein Tyrosine Kinase, Family, Tyrosine

Phosphorylation, Regulation, Signal Transduction, Review

Send correspondence to: Alexander Y. Tsygankov,

Department of Microbiology & Immunology, Temple
University School of Medicine, 3400 N. Broad Street,
Philadelphia, PA 19140, USA, Tel: 215-707-1745, Fax:
215-707-5205, E-mail: tsygan@[Link]

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