Cell-Cell Interaction
Cell-cell communication via cell adhesion molecules is critical for assembling cells into tissues, controlling cell shape and cell function (together with cellmatrix interactions
cell-cell interaction sites cell-matrix interaction sites
basement membrane
Cell-Cell Interaction
Major cell-cell adhesion sites can be visualized by electron microscopy Tight junctions Adherens junctions Desmosomes
Tight junction Adherens junction Gap junction
Mikrovili
Desmosom
Hemidesmosom
Basallamina
Cell-Cell Interaction
Major cell-cell adhesion sites can be visualized by electron microscopy Tight junctions Adherens junctions Desmosomes Cells can also interact without forming visible adhesion sites most important cell adhesion molecules: Cadherins (all cells) Ig-superfamily (ubiquitous, enriched in the nervous system) Selectins (interaction of leukocytes with endothelial cells
Cell-Cell Interaction
Major cell-cell adhesion sites can be visualized by electron microscopy Tight junctions Adherens junctions Desmosomes Cells can also interact without forming visible adhesion sites most important cell adhesion molecules: Cadherins (all cells) Ig-superfamily (ubiquitous, enriched in the nervous system) Selectins (interaction of leukocytes with endothelial cells
Cadherins
Ca2+-dependent cell-cell adhesion proteins,
epressed in almost all cells of vertebrates and invertebrates
Transmembrane proteins characteristic structural feature:
- tandem repeats of homologous domains (CAD-domains):
-
length of about 110 amino acids -sheet structure, distantly related to immunoglobulin-fold
The structure of cadherins
crystal structure of the extracellular domain from C-Cadherin (Xenopus)
EC1-EC5: CAD-domains
Leckband, Prakasam (2006) Annu Rev Biomed Eng 8, 259
Cadherins
large superfamily (> 100 different genes identified in the vertebrate genome)
classic cadherins
E-, N-, P-Cadherin
actin
desmosomal cadherins
desmocollin desmoglein
intermediatefilaments
linked to cytoskeleton
Cadherins
large superfamily (> 100 different genes identified in the vertebrate genome) protocadherins
a-Pcdh (CNR-Cadherin)
7TM-cadherin (Flamingo)
in many cases not associated with the cytoskeleton
Laminin-G-DomneRepeats
EGF-Repeats
Fat-family
Classical Cadherins (Examples)
Junction Phenotype when Inactivated in Mice Association
Name
Main location
E-cadherin
epithelia
epithelial embryonic lethal, adherens mice die at blastocyst stage Junctions (AJ) embryonic lethal, heart defects embryonic lethal, apoptosis of endothelial cells bone and behavioral abnormalities, resistant to rheumatic arthritis
N-cadherin
neurons, heart, muscle, AJ-like eye lens structures, synapses adherens junctions
VE-cadherin Endothelzellen cadherin-11 mesenchymal cells, neural crest cells, several cancer types
Features of classical cadherins
engaged in homophilic interactions five extracellular CAD-domains specificity determined by the most N-terminal domain
associated with the cytoskeleton via various linker proteins: b-Catenin is required to link Cadherin to other anchor proteins various anchor proteins connect b-Catenein to the actin filaments (previously a-catenin had been considered to be the major linking protein) p120-Catenin is required for stable location of Cadherin at the plasma membrane (inhibits endocytosis)
Cadherin-mediated cell cell adhesion
(prevalent structural model) cell 1
b-Catenin a-Catenin
cell 2
intercellularspace
vinculin VASP
F-actin a-actinin p120-catenin
cadherins
actin filaments adapter proteins
adapter proteins
actin filaments
Major functions of classical cadherins :
cell shape, tissue architecture cell polarity cell-sorting signaling
classical cadherins (E-cadherin) form the adherens junctions (AJs) between epithelial cells
Major functions of classical cadherins :
cell shape, tissue architecture cell polarity cell-sorting signaling
Cell-Sorting
changes of cadherin expression during development of the neural tube and neural crest cells
Ektoderm infolding of the neural tube neural tube closure
neural crest cells
expression of E-Cadherin expression of Cadherin-6B expression of N-Cadherin expression of Cadherin-7
cell adhesion by cadherins is strictly regulated
examples: - migration of neural crest cells:
E-cadherin expression is down-regulated ( disassembly of AJs) and substituted by other cadherins ( allowing cell contact during migration)
- gastrulation:
inhibited, if E-cadherin is not down-regulated (Cells cannot leave the ectoderm)
- pathological conditions:
Carcinomas down-regulate the expression of E-Cadherin, which is often substituted by N-cadherin
Major functions of classical cadherins :
cell shape, tissue architecture cell polarity cell-sorting signaling
Signaling via Cadherins / Catenins
examples:
1.
Modulation of kinase/ phosphatase activities by binding to cadherin/catenin complexes
N-cadherin activates E-cadherin inhibits VE-cadherin: FGF-receptors FGF- and EGF-receptors Co-receptor for VEGF, loss of VE-cadherin leads to apoptosis of endothelilal cells
2.
Wnt-signaling
b-Catenin has two functions:
Wnt
1) component of cadherin-mediated cell-cell contacts
Fzd
Dsh
cadherin -Catenin
GSKactive
GSK inactive
-Catenin P
proteasomal degradation
2) component of Wnt-pathway
-Cat LEF1/TCF
Non-Classical Cadherins (Examples)
Name Main Location Functions
Desmosomal Cadherins (they are associated with intermediate filaments)
Desmoglein, Desmocollin skin (desmosomes) inactivation results in detachment of the skin, hyperproliferation, abnormal differentiation
Protocadherins
PAPS
(paraxial protocadherin)
paraxial mesoderm neurons (synapses)
cell movements during gastrulation three gene clusters encoding more than 50 cadherins. All members of one cluster contain the same C-terminal domain. Not connected to cytoskeleton deafness, if inactivated
-, -,- Pcdhs
(clustered protocadherins)
Cadherin 23 Protocadherin 15
inner ear
Others
Flamingocadherins FAT, Dachsous epithelia, associated with junctions epithelia, associated with junctions planar cell polarity inactivation in Dros. results in overgrowth of imaginal discs, defects in differentiation and morphogenesis, formation of tumors
Desmosomes
cadherin-family adhesion proteins intermediate filaments dense plaque of anchor proteins
Desmosomes
plakoglobin
cadherin-family adhesion proteins intermediate filaments dense plaque of anchor proteins
desmoplakin
(= g-catenin)
plakophilin
desmoglein desmocollin
intermediate filaments
plasma membrane cadherin-family adhesion proteins
Planar cell polarity (PCP)
Polarization of cells within the plane of a cell sheet
PCP is best investigated in Drosophila wing epithelium flamingocadherin
mutant clone (marker: wing hairs)
Seifert, Mlodzik (2007) Nat Rev Genet 8, 126
wing epithelial cells
Cell-Cell Interaction
the most important cell adhesion molecules:
Cadherins (all cells) Ig-superfamily (ubiquitous, enriched in the nervous system) Selectins ( interaction of leukocytes with endothelial cells)
Cell Adhesion Molecules of the Immunoglobulin (Ig)-Superfamily:
Large, ancient superfamily All members are characterized by the presence of (multiple) Ig-like domains that were first identified in antibodies.
Two layers of antiparallel b-sheets are folded on top of each other. The two layers are connected by one disulfide bond.
schematic representation of immunoglobulin G
Cell Adhesion Molecules of the Immunoglobulin (Ig)-Superfamily:
In addition to cell adhesion molecules and antibodies, Ig-like domains are found in many proteins. Ig-like domains are encoded in 765 human genes! Examples are: - T-cell receptor, CD4, MHC I, MHC.II - FGF-receptor
Cell Adhesion Molecules of the Immunoglobulin (Ig)-Superfamily:
Cell adhesion is not Ca2+ -dependent (in contrast to the cadherins). Cell adhesion can be - homophilic (between like molecules) or - heterophilic (between different molecules) Binding is more stable than binding between cadherins!
plasma membrane
plasma membrane
Possible binding pattern between two Ig-CAMs
intercellular space
Some Types of Ig-Superfamily Cell Adhesion Molecules
Name neuronal CAMs
NCAM L1 (NgCAM) nerves cell adhesion, -migration, axonal growth and guidance
Main Location
Typical Function
non-neuronal CAMs
ICAMs (intercellular adhesion molecules) VCAMs (vascular cell adhesion molecules) PECAM (platelet endothelial cell adhesion Molecule) Nectins leukocytes, lymphocytes, endothelial cells endothelial cells platlets; endothelial cells adherens junctions together with cadherins essential for adherens junctions assembly adhesion of lymphocytes and leukocytes to endothelial and epithelial cells (inflammation response)
Schematic Structure of Some Ig-CAMs
L1
c c c c c c
F11/Contactin
c c c c c c c c c c c c c c
Ig-domain FNIII-domain GPI-anchor
NCAM
c c c c c c c c c c c c c c c c c c c c
c c c c c c
ICAM-1
c c c c c c c c c c
ICAM-2
c c c c
Nectin-1
c c c c c c
Biological functions of neuronal CAMs (examples):
cell-cell adhesion (neuron-neuron, neuron-glia) regulation of signal transduction processes (e.g. activation of FGF-receptors via interaction with NCAM) cell migration neurite outgrowth
- axon fasciculation - axon guidance and sorting along nerve fascicles - branching of axon bundles
Neurite outgrowth
receptors for soluble factors (growth factors, chemoattractants)
Cell-substrate interactions (integrins, laminins)
cell-cell interactions (CAMs, cadherins)
Cell-substrate interactions (integrins, laminins)
changes in fasciclin-II expression during axonal growth
three grasshopper neurons
fasciclin-II
(NCAM equivalent in insects)
NCAM (neural cell adhesion molecule)
Ig-superfamiliy protein with - 5 Ig-domains - 2 Fibronectin-typeIII domains multiple forms by alternative spicing (120 - 180 kDa):
- transmembrane proteins - lipid-bound proteins (GPI-anchor)
homophilic interaction during embryogenesis expression in many tissues, in the adult mainly expresseed in the nervous system (and neuromuscular junctions) vertebrate NCAMs: modification by polysialic acids (PSA)
NCAM-modification with polysialic acid (PSA)
HO H HO HO
CH2 HO
COOH
OH
sialic acid
H2 N
2 different polysialyltransferases attach PSA-chains to domain Ig5
Biological Functions of Polysialic Acid
- modulation of cell adhesion strength - modulation of fasciculation and branching of axons trajectory of motor axons in the embryonic chicken hindlimb
control
neuraminidase treated
olfactory bulb
wild type NCAMmutant
Neural Cell Recognition molecule L1
many mutations in the L1 gene have been described in humans leading to a broad spectrum of diseases:
normal
- mental retardation (IQ < 20 - 50) - hydrocephalus - corpus callosum hypoplasia - absence or diminution of the corticospinal tract - paralysis of lower extremities
L1-mutant
corticospinal tract (CST) at the level of the pyramids in the medulla
