Cell Adhesion Molecules.

There are a huge variety and number of CAMs. This diversity allows discriminate binding of cell types to other cell type ad cells to extra-cellular matrix components. It is apparent that CAMs are not simply molecules that stick cell together into tissues, but that many of them perform signalling functions too. The following is a summary of the salient features of the main families. For a very recent and much more complete source, see Kreis & Vale (1999).

Selectins.

There are three types of Selectins, E, L, & P. They are members of the C-type lectin super-family. Lectins are proteins that bind carbohydrate determinants either in solution or more often as part of glycoproteins. The selectins mediate calcium dependent adhesion between leucocytes, platelets and endothelial cells.

Figure 1. Modular organisation of selectin structure. The N-terminal lectin domain is followed by an EGF (epidermal growth factor) – like domain and then a variable number of so called complement repeat (CR) subunits. These are followed by a transmembranous domain and finally a C-terminal cytoplasmic domain

Name (and alternatives)	Expressed on surface of:-	Ligand bound	Cell carrying the Ligand
E-Selectin ELAM-1	Endothelial Cells	Sialylated, fucosylated residues. On ESL-1, L-selectin, PSGL-1	Neutrophils
L-Selectin LEC-Cam-1, LAM-1, gp90^mcl	Leucocytes	Fucosylated glycans. On CD43, MadCAM-1	Leukocytes
P-Selectin CD62, PADGEM, GMP-140	Platelets, Endothelial Cells	? On PSGL-1	Neutrophils, monocytes

Table 1. Selectin carrying cell type and the tissues recognised.

Figure 2. Margination of neutrophils after the cell is slowed in the blood stream by selectin interaction, first by rolling, then by actual adhesion. Neutrophils signal to the endothelium leading to local release of endothelial cell contact allowing neutrophil to squeeze out of blood stream and into the damaged tissue where chemotaxis guides the neutrophil towards the source of inflamation, or bacterial source. (see Godin et al, 1999). LFA-1 (an integrin pair) is also important in the fomation of tight adhesion (see later).

The selectins mediate adhesion between endothelium and neutrophils prior to margination of the neutrophils into tissues where the lesion is present. Chemo-attractants such as Fet-Met-Leu-Phe diffucng from the invading bacteria stimulate this possibly through the endothelial cells, but the details are not clear.

ICAMS

ICAMS (intercellular adhesion molecules) belong to the Ig-like super-family of adhesion molecules. There are currently 5 recognised members of this group each sharing a similar structure but differing w.r.t. the number of Ig-like domains. ICAM-1 is the ligand that associates leucocytes to other cell types. It is up-regulated upon stimulation with interferon and other inflammatory stimuli. LFA-1 (an aL,b2 intergrin) on leucocytes is the target molecule. ICAM-1 is the receptor for the rhinoviruses that cause the common cold, and more seriously, the receptor for Plasmodium falciparum (which causes malaria). There are many other members of the Ig-like adhesion molecule super-family including:-N.CAMs (neural), the DCC family, UNC-5 family and TAG-1 (see Kriess & Vale, 1999 for details).

Figure 3 Other ICAM members are ICAM-2 which has 2 Ig-like domains, ICAM-3 which has 5, ICAM-4, 2 and telencephalin, has 9.

Integrins.

Integrins are a vast collection of hetero-dimeric adhesion molecules, expressed on virtually all metazoan cell types. In humans there are at least 8 different b chains and 16 different a-chains. These could give rise to a theoretical 128 combinations and there is evidence for at least 22 combinations, each of which seems to have its own particular function. For example the aL,b2 intergrin otherwise known as LFA-1 (or CD11a/CD18) is restricted to leucocyte and binds ICAM molecules.

Figure 4. The structure of integrins. Not all a-chains are cleaved as shown here. The divalent binding region of the a-chain is formed into a “seven unit propeller” structure. Divalent cations (usually calcium) are required for ligand binding. The integrins are bound by a number of other proteins within the plain of the membrane, these include FAK and IAP (see below).

The intergrins signal both ways across the plasma-membrane. Binding extracellular ligands such as the extra-cellular matrix signals the cytoskeleton through Focal Adhesion Kinase (FAK) pathway. Also the cytoskeleton binding to the integrin pair through the b-chain (via a-actinin, talin complex, see fig 5) causes a conformational change to occur in the extracellular domain of the integrin causing them to be ‘switched on” that is their affinity for their ligand is now greatly increased.

The function of integrins is also modulated by integrin associated proteins (IAPs). Patients without IAP have recurrent infections very possibly as a result of neutrophil dysfunction. They cannot get to the site of infection quickly.

Figure 5.

Cytoplasmic attachment of integrins to the actin cytoskeleton. Talin and a-actinin bind directly to the b-chain of integrins. Talin and a -actinin are both active as dimers bind F-actin (microfilaments). Talin and a-actinin bind vinculin another actin binding protein which binds yet another actin binding protein tensin. Signalling from outside causes the complex to form, and complex formation signals through the integrins to allow them to bind. So there is bi-directional communication.

Cadherins

The cadherins mediate cell-cell homotypic, calcium dependent adhesion. That is at adhesions such as desmosomes a cadherin from one cell binds to a cadherin from another cell across the space that separates them. A complex of protein similar to those that bind to the integrin complex exist at the cytoplasmic side of the cadherin junction. Like the integrins the cadherins also are sites of signalling, this time through the intriguing wnt/APC pathway (see figure 7) (Gumbiner, 1997).

Figure 6. Cadherin adhesion complex.

Figure 7. The Wnt/APC pathway. Adhesion signals through b-catenin to increase transcription of several genes via LEF-1 transciption factors.

References

Godin, C., Caprani, A., Dufaux, J. and Flaud, P. (1999). Interaction between neutrophils and endothelial cells. J.Cell Sci. 106; 441-452.

Gumbiner, B.M. (1997). Carcinogenesis: A balance between b-catenin and APC. Curr.Biol. 7; R443-R446.

Kreiss, T. & Vale, R. (1999) Guidebook to the Extracellular matrix, anchor, and adhesion proteins. Oxford Univ. Press. (Ed.Univ.Library code QP552.E95Gui.).

Any questions? SKM@srv4.med.ed.ac.uk Tel 0131 650 3714