Integrins
Integrins are widely expressed cell surface adhesion molecules that mediate cell-extracellular matrix and cell-cell interactions. Integrins are the principal receptors on animal cells for binding most extracellular matrix proteins like collagens, fibronectin and laminins. T cells have little apparent adhesion to integrin ligands. However, upon activation through T cell receptor or chemokine receptors, a cascade of signaling events leads to enhanced integrin functionality, known as "inside-out" signaling. it involves the translocation of proteins to integrin cytoplasmic domains and the assembly of multiprotin complexes. The formation of these complexes results in activation and clustering of integrins, thus enhacning both affinity and avidity of integrins for their ligands.
Structure: Integrins are composed of 2 noncovalently associated transmembrane glycoprotein subunits called alpha and beta. Integrins have been organized into eight distinct subfamilies based on beta subunit assocations. Members of the beta 1 subfamily (also called VLA proteins) each contain the beta1 subunit in association with one of at least nine difference alpha subunits. In the beta2 subfamily, there are 3 distinct alpha subunits which associate with beta2 (CD11/CD18). The other groups associated with the beta3-beta8 subfamilies have various roles and functions.
Regulation of Integrin Expression: Integrin 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 actin cytoskeleton 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 tyrosine kinases.
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.
Integrins and Disease: During adhesion and transmigration, integrins of the beta1 and beta2 family, such as VLA4 (alpha4b eta1) or LFA-1 (alphaLbeta2), bind to their endothelial counter-receptors vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Numerous studies have shown that adhesion of lymphocytes to inflamed brain vessels during EAE is mianly mediated by the VLA-4-VCAM-1 system, although there is also evidence pointing to the role of the LFA-1-ICAM-1 interaction.
Therapeutics: Natalizumab is a humanized anti-alpha4 integrin antibody that is approved for treatment of both MS and Crohn's disease.
The HIV cell surface glycoprotein, gp120, was shwon to directly bind alpha4beta7 potentially facilitating HIV entrance into CD4 T cells. Several but not all integrin blocking antibodies reduced viral replication in CD4 T cell cultures.
