Cell adhesion, Tight and gap junction.

Cell-Cell Interactions:

Direct interactions between cells, as well as between cells and the extracellular matrix, are
critical to the development and function of multicellular organisms. Some cell-cell
interactions are transient, such as the interactions between cells of the immune system and
the interactions that direct white blood cells to sites of tissue inflammation. In other cases,
stable cell-cell junctions play a key role in the organization of cells in tissues. For example,
several different types of stable cell-cell junctions are critical to the maintenance and
function of epithelial cell sheets. In addition to mediating cell adhesion, specialized types of
junctions provide mechanisms for rapid communication between cells. Plant cells also
associate with their neighbors not only by interactions between their cell walls but also by
specialized junctions between their plasma membranes.

Adhesion Junctions

Cell-cell adhesion is a selective process such that cells adhere only to other cells of specific
types. This selectivity was first demonstrated in classical studies of embryo development,
which showed that cells from one tissue (e.g., liver) specifically adhere to cells of the same
tissue rather than to cells of a different tissue (e.g., brain). Such selective cell-cell adhesion
is mediated by transmembrane proteins called cell adhesion molecules, which can be
divided into four major groups:

the selectins, the integrins, the immunoglobulin (lg) superfamily (so named because they
contain structural domains similar to immunoglobulins), the cadherins.

Cell adhesion mediated by the selectins, integrins, and most cadherins requires Ca2+, Mg2+
or Mn2+, so many adhesive interactions between cells are divalent cation-dependent. The
selectins mediate transient interactions between leukocytes and endothelial cells or blood
platelets.

There are three members of the selectin family: L-selectin, which is expressed on
leukocytes; E-selectin, which is expressed on endothelial cells; and P-selectin, which is
expressed on platelets.

The selectins recognize cell surface carbohydrates. One of their critical roles is to initiate
the interactions between leukocytes and endothelial cells during the migration of leukocytes
from the circulation to sites of tissue inflammation. The selectins mediate the initial
adhesion of Leukocytes to endothelial cells. This is followed by the formation of more stable
adhesions in which integrins on the surface of leukocytes bind to intercellular adhesion
molecules (ICAMs), which are members of the Ig superfamily expressed on the surface of
endothelial cells. The firmly attached leukocytes are then able to penetrate the walls of
capillaries and enter the underlying tissue by migrating between endothelial cells.
Homophilic adhesion is when identical cell adhesion molecules (CAMs) on different cells
bind to each other, while heterophilic adhesion involves one cell's CAM binding to a
different type of CAM on an adjacent cell. Both processes use CAMs, which are molecules
on the cell surface that mediate connections to other cells or the extracellular matrix, but
they differ in the specificity of the interaction.

The binding of ICAMs to integrins is an example of a heterophilic interaction in which an

adhesion molecule on the surface of one cell (e.g., an ICAM} recognizes a different
molecule on the surface of another cell (e.g., an integrin). Other members of the Ig
superfamily mediate homophilic interactions in which an adhesion molecule on the surface
of one cell binds to the same molecule on the surface of another cell. Such homophilic
binding can lead to selective adhesion between cells of the same type. For example, nerve
cell adhesion molecules (N-CAMs) are members of the Ig superfamily expressed on nerve
cells, and homophilic binding between N-CAMs contributes to the formation of selective
associations between nerve cells during development. There are more than 100 members of
the Ig superfamily, which mediate a variety of cell-cell interactions.

The fourth class of cell adhesion molecules is the cadherins. Cadherins are involved in
selective adhesion between embryonic cells, formation of specific synapse in the nervous
system, and are the proteins primarily responsible for the maintenance of stable junctions
between cells in tissues.

Cadherins are a large family of proteins (about 80 members) that share a highly conserved
extracellular domain that mediates largely homophilic interactions. For example, E-cadherin
is expressed on epithelial cells so homophilic interactions between E-cadherins lead to the
selective adhesion of epithelial cells to one another. It is noteworthy that loss of E-cadherin
can contribute to the development of cancers arising from epithelial tissues, illustrating the
importance of cell-cell interactions in controlling cell behavior.

Different members of the cadherin family, such as N-cadherin (neural cadherin) and P-
cadherin (placental cadherin), mediate selective adhesion of other cell types. There are
several subfamilies of cadherins (classic cadherins, desmosomal cadherins, fat-like
cadherins, and seven transmembrane domain cadherins) which differ primarily in their
transmembrane and cytosolic domains.

Adherens junctions: In adherens junctions, cadherins link to actin filaments. β-catenin

binds to the cytosolic tails of the cadherins. β-catenin also binds α-catenin, which binds both
actin filaments and vinculin. This forms a direct link between the transmembrane cadherins
and the actin cytoskeleton. A second protein, p120, also binds the cytosolic tails of cadherins
and regulates the stability of the junction.

The cell-cell interactions mediated by the selectins, integrins, and most members of the Ig
superfamily are transient adhesions in which the cytoskeletons of adjacent cells are not
linked to one another.

Stable adhesion junctions involving the cytoskeletons of adjacent cells instead are based
largely on cadherins. These cell-cell junctions are of two types: adherens junctions and
desmosomes. At these junctions, classic and desmosomal cadherins are linked to actin
bundles and intermediate filaments, respectively, by the interaction of their cytosolic tails
with β-catenin or desmoplakin. The role of the cadherins in linking the cytoskeletons of
adjacent cells is thus analogous to that of the integrins in forming stable junctions between
cells and the extracellular matrix.

The basic structural unit of an adherens junction includes , β-catenin and α-catenin in
addition to the classic transmembrane cadherins. ,β-catenin binds directly to the cytosolic
tail of the cadherins. αcatenin binds to ,βcatenin as well as to actin filaments and actin
filament-binding proteins, such as vinculin. Thus α and, βcatenin directly link the actin
cytoskeleton of one cell, through the transmembrane cadherins, to the actin
cytoskeleton of an adjacent cell.
Cadherins recruit actin-binding proteins, such as vinculin, to begin assembly of a mature
adherens junction.

Tight Junctions

Tight junctions are critically important to the function of epithelial cell sheets as barriers
between fluid compartments. For example, the intestinal epithelium separates the lumen of
the intestine from the underlying connective tissue, which contains blood capillaries. Tight
junctions play two roles in allowing epithelia to fulfil such barrier functions. First, tight
junctions form seals that prevent the free passage of molecules (including ions) between the
cells of epithelial sheets. Second, tight junctions separate the apical and basolateral domains
of the plasma membrane by preventing the free diffusion of lipids and membrane proteins
between them. Consequently, specialized transport systems in the apical and basolateral
domains are able to control the traffic of molecules between distinct extracellular
compartments, such as the transport of glucose between the intestinal lumen and the blood
supply. While tight junctions a revery effective seals of the extracellular space, they provide
minimal adhesive strength between the apposing cells, so they are usually associated with
adherens junctions and desmosomes in a junctional complex.

Tight junctions are the closest known contacts between adjacent cells. They were originally
described as sites of apparent fusion between the outer leaflets of the plasma membranes,
although it is now clear that the membranes do not fuse. Instead, tight junctions are formed
by a network of protein strands that continues around the entire circumference of the cell.
Each strand in these networks is composed of transmembrane proteins of the claudin,
occludin, and junctional adhesion molecule (JAM) families. All three of these proteins
bind to similar proteins on adjacent cells, thereby sealing the space between their plasma
membranes. The cytosolic tails of claudins, occludins, and JAMs are also associated with
proteins of the zonula occludens family, which link the tight junction complex to the actin
cytoskeleton and hold the tight junction in place on the plasma membrane.
Gap Junctions

The activities of individual cells in multicellular organisms need to be closely coordinated.

This can be accomplished by signaling molecules that are released from one cell and act on
another. However, within an individual tissue, such as the liver, cells are often linked by
gap junctions, which provide direct connections between the cytoplasms of adjacent
cells. Gap junctions are open channels through the plasma membrane, allowing ions
and small molecules (less than approximately a thousand daltons) to diffuse freely
between neighboring cells, but preventing the passage of proteins and nucleic acids.
Consequently, gap junctions couple both the metabolic activities and the electric responses
of the cells they connect. Most cells in animal tissues-including epithelial cells, endothelial
cells, and the cells of cardiac and smooth muscle communicate by gap junctions. In
electrically excitable cells, such as heart muscle cells, the direct passage of ions through gap
junctions couples and synchronizes the contractions of neighboring cells. Gap junctions also
allow the passage of some intracellular signaling molecules, such as cAMP and Ca2+,
between adjacent cells, potentially coordinating the responses of cells in tissues.

Gap junctions are constructed of transmembrane proteins of the connexin family, which
consists of at least 21 different human proteins. Six connexins assemble to form a cylinder
with an open aqueous pore in its center. Such an assembly of connexins, a connexon, in
the plasma membrane of one cell then aligns with a connexon of an adjacent cell,
forming an open channel between the two cytoplasms. The plasma membranes of the
two cells are separated by a gap corresponding to the space occupied by the connexin
extracellular domains-hence the term "gap junction". Many cells express more than one
member of the connexin family, and combinations of different connexin proteins may give
rise to gap junctions with varying properties. Specialized assemblies of gap junctions occur
on specific nerve cells in all eukaryotes and form an electrical synapse. The individual
connexons within the electrical synapse can be opened or closed in response to several types
of signals but, when open, allow the rapid passage of ions between the two nerve cells. The
importance of gap junctions- especially in the nervous system- is illustrated by the number
of human diseases associated with connexon mutations.

Gap junctions consist of assemblies of six connexins, which form open channels
through the plasma membranes of adjacent cells

Plasmodesmata:

Adhesion between plant cells is mediated by their cell walls rather than by transmembrane
proteins. In particular, a specialized pectin-rich region of the cell wall called the middle
lamella acts as a glue to hold adjacent cells together. Because of the rigidity of plant cell
walls, stable associations between plant cells do not require the formation of cytoskeletal
links such as those provided by the desmosomes and adherens junctions of animal cells.
However, adjacent plant cells communicate with each other through cytoplasmic
connections called plasmodesmata (singular, plasmodesma). Although distinct in structure,
plasmodesmata function analogously to gap junctions as a means of direct communication
between adjacent cells in tissues.

Plasmodesmata form from incomplete separation of daughter cells following plant cell
mitosis. At each plasmodesma, the plasma membrane of one cell is continuous with that of
its neighbor, creating a channel between the two cytosols. An extension of the smooth
endoplasmic reticulum passes through the pore, leaving a ring of surrounding cytoplasm
through which ions and small molecules are able to pass freely between the cells.
Plasmodesmata are dynamic structures that can open or close in response to appropriate
stimuli, permitting the regulated passage of macromolecules between adjacent cells. In
addition, there is evidence that proteins and lipids can be targeted to plasmodesmata in
response to specific signals. Plasmodesmata may thus play a key role in plant development
by controlling the trafficking of regulatory molecules, such as transcription factors or RNAs,
between cells.

In a plasmodesma, the plasma membranes of neighboring cells are continuous,

forming cytoplasmic channels through the adjacent cell walls. An extension of the
endoplasmic reticulum usually passes through the channel.