Cells adhere to each other and to the extracellular matrix through cell surface proteins called cell adhesion molecules (CAMs). Tissue architecture is established and maintained to a large extent by specific affinities of cell surface glycoproteins for molecules in the extracellular matirx or on the surface of adjacent cells. CAMs function not only to fix cells in specific locations within tissues adn regulate their movement but also to translate biochemical information from the extracellular environment through the activation of intracellular signaling pathways leading to specific cell functional resposnes. Some CAMs are Ca2+ dependent whereas others are Ca2+ independent.  Adhesion molecules can be divided into four families: (1) immunoglobulin-like adhesion molecules, (2) selectins, (3) cadherins and (4) integrins.

Cadherins are the major CAMs responsible for Ca2+ dependent  cell-cell adhesion in vertebrate tissues. There are many types of cadherins which make up the cadherin family and cells in culture can sort themselves out according to the type and level of cadherins they express.  Most cadherins are single pass transmembrane glycoproteins that have a large extracellular part of their polypeptide chain folded into 5 or 6 cadherin repeats. Ca2+ ions are positioned between each pair of cadherin repeats. The more Ca2+ ions bound, the more rigid the structure. 

Selectinsarenother major CAM responsible for Ca2+ independent cell-cell adhesion are the selectins which are cell surface carbohydrate binding proteins (lectins) which mediate cell-cell adhesion in the bloodstream. For example, L-selectins are found on lymphocytes which recognize oligosaccharides expressed on endothelial cells in lymphoid organs causing the lymphocytes to become trapped. Conversely, at sites of inflammation, endothelial cells switch on expression of selectins which recognize the oligosaccharides on lymphocytes and platelets. 

Selectins often work together with a third type of cell adhesion molecule called integrins. Selectins and integrins act in sequence to let leave the bloodstream and enter tissues. The selectins mediate a weak adhesion which allows the white blood cell to roll along the surface of the blood vessel propelled by the flow of blood. This rolling continues until the blood cell activates its integrins (cadherins are not involved in leukocyte recruitment) which causes the cell to bind strongly to the endothelial cell surface and to crawl out of the blood vessel between adjacent endothelial cells.

ntegrinsare the principal receptors on animal cells for binding most  like collagens, fibronectin and laminins. Integrins are composed of 2 noncovalently associated transmembrane glycoprotein subunits called alpha and beta. The binding to their ligands depend on extracellular divalent cations like Ca2+ reflecting the presence of divalent cation binding domains in the extracellular part of the subunits. Integrins bind to a matrix protein outside the cell and to the  via an anchor protein inside the cell. The binding to their ligands is of low affinity but high capacity. (binding depends on a large number of weak adhesions). The clustering of integrins at sites of contact with the matrix can activate intracellular signaling pathways. Many of the signaling functions of integrins depend on a cytoplasmic protein tyrosine kinase called focal adhesion kinase (FAK). When integrins cluster at sites of cell-matrix contact, FAK is recruited to focal adhesions by intracellular anchor proteins such as talin or paxillin. The clustered FAK molecules cross phosphorylate each other on a specific tyrosine for members of the Src family of cytoplasmic . A cell can also control integrin ligand interactions from within (inside out signaling) which allows regulated adhesion. This is important for example with T lymphocytes where the weak binding of a T lymphocyte to its specific antigen on the surface of an antigen presenting cell triggers intracellular signaling pathways that activate its integrins. The activated integrins enable the T cell to remain in contact long enough to become fully stimulated.

Whereas cadherins, slectins and integrins all depend on extracellular Ca2+ to function in cell adhesion, a major CAM which is Ca2+ independent are the N-CAMs or “neural cell adhesion molecules” which are expressed in a variety of cells including most nerve cells. 

Most cadherins function as transmembrane adhesion proteins that indirectly link the of the cells they join. This occurs in Cell Junctions like the adherens junctions where the cytoplasmic tails of cadherins interacts indirectly with actin filaments by means of a group of intracellular anchor proteins called “catenins” and with desmosomes where the cytoskeleton is intermediate filaments.

• Occluding junctions: include the tight junctions whose role is particularly prominent in the small intestine where they prevent transport proteins at the apical surface of the epithelia cell (surface facing the lumen) from mixing with those in the basolateral surfaces of the cell. In addition tight junctions insure that spaces between epithelia cells are sealed so that transported molecules cannot diffuse back into the gut. Major transmembrane proteins in a tight junction include the claudins and occludins.

• • Anchoring junctions: connect the cytoskeleton of a cell to the cytoskeleton of other cells using the transmembrane protein cadherin or to the extracellular matrix () through the use of the TM protein integrin. In both cases, there is an intracellular coupling to either actin or intermediate filaments depending on the type of intracellular anchor proteins involved. The various anchoring junctions are contained in the chart below:

  Cell-Cell	TM protein	Extracellular Ligand	Intracellular Ligand	Intracellular anchor proteins
  Adherens junction	cadherin	cadherin in other cell	actin filaments	? actinin, catenins, more
  Desmosome	cadherin	desmogleins & desmocolins	intermediate filaments	desmoplakins
  Cell-Matrix
  Focal adhesion	integrins	extracellular matrix proteins	actin filaments	? actinin, more
  Hemidesosome	integrins	extracellular matrix proteins	intermediate filaments

  • Communicating junctions: include the gap junctions which form channels through transmembrane proteins called connexins. 6 connexins are required to form a channel (called a “connexon”) and when the connexons in the PM of 2 cells in contact are aligned, they form a continuous aqueous channel that connects the two cell interiors.