Integrins

Integrins connect cells with other cells and with the extracellular matrix (adhesion molecules). Furthermore, they play a role in signal transduction between cells and their environment. Other proteins play an important role in these interactions:

• Cadherins
• CAMs (cell adhesion molecules, e.g. ICAM-1 )
• Selectins.

The extracellular, portion (protein domain) of these transmembrane proteins has binding sites with the"RGD" recognition feature(Arg-Gly-Asp) (RGD sequence) such as fibronectin (in fibroblasts), or "non-RGD proteins" such as intercellular adhesion molecules (ICAMs), collagens and laminin (in epithelial cells).

Chemically, an integrin consists of two subunits (alpha and beta subunits) that are linked together. For the alpha and beta subunits there are again different subtypes (e.g. beta 1, beta 2 and others). Some integrins are expressed by leukocytes and play an important role in the process of leukocyte emigration.

One of these integrins is Lymphocyte Functional Antigen-1 (LFA-1 = CD11a; see Psoriasis vulgaris below), which is expressed by all leukocytes.

In contrast, another integrin, MAC-1(CD11b), is found only on granulocytes (see also under PRRs).

Integrins mediate the firm attachment of leukocytes to the vascular endothelium, a prerequisite for leukocyte emigration (migration) from blood vessels. This important function of integrins was discovered in the context of a rare immune disease, leukocyte adhesion deficiency-I (LAD-I). Affected patients suffer from severe, recurrent infections because their leukocytes do not express functional beta1 integrins due to a genetic defect, and their migration into tissues is thus severely impaired.

In psoriatic patients, inflammatory T cells have been shown to produce the receptor alpha1-beta1 integrin (VLA-1) directed against collagen IV (collagen of the basement membrane). This integrin is expressed on epidermal lymphocytes in lesional (not unaffected) skin and appears to play a role in the overcoming of the basement membrane by these lymphocytes (see epidermotropy below).

Integrin alpha-6/beta-4" occupies a structural role in hemidesmosomes of epithelial cells and is required for the regulation of keratinocyte polarity and motility. Mutaions in the coding gene lead to localized suprabasal epidermolysis bullosa simplex as well as to epidermolysis bullosa junctionalis with pyloresatresia.

The angiogenesis inhibitor cilengitide inhibits several integrins and is used in clinical trials for malignant melanoma.

Note: Cilengitide inhibits the integrins alpha-5β3 and alpha-5β5 and thus the formation and growth of tumorigenic blood vessels(angiogenesis) and thus the growth and spread of tumor cells (preparation was not approved for the treatment of glioblastoma!).