Integrins

Integrins belong to a superfamily of transmembrane glycoprotein receptors involved in mediating cell to cell and cell to ECM interactions. They exist as heterodimers composed of a and p subunits bound by non-covalent bonds. To date, 18 a subunits and 8 p subunits have been identified, which can associate to form 24 unique complexes (Table 1) with the different ap combinations possessing distinct ligand binding specificities [7, 8]. There are three distinct regions in each integrin subunit with each subunit containing an extracellular domain, a transmembrane domain and a short intracellular domain.

The extracellular regions of the a and p subunits together form the ligand binding site. The most common ligands for integrins are large ECM proteins such as laminin, fibronectin, collagen and vitronectin. These ECM proteins (except for laminin and collagen) have a common arginine-glycine-aspartic acid (RGD) motif, whereas integrins recognise laminin and collagen through cryptic RGD sites. In addition, there are some integrins that interact with other adhesion molecules such as cadherins, intracellular adhesion molecules (ICAMs) and vascular adhesion molecules (VCAMs), expressed on leukocytes and endothelial cells. By grouping the integrins according to integrin ligand specificity, the collagen binding integ-rins are a1p1, a2p1, a3p1, a10p1, a11p1 and a6p4, the laminin binding integrins are a1p1, a2p1, a3p1, a6p1, a7p1 and a6p4 and the RGD recognising integrins are a5p1,avp1, avp3, avp5, avp6, avp8 and aIIbp3. However, integrins can frequently bind several ligands (as outlined in Table 1), permitting redundancy in signalling as multiple integrins are generally present on any particular cell surface.

Integrin

Ligand

alßl

Collagen IV and VI, Laminin-1

a2ß1

Collagen I, Laminin-1,-2 and -10

Collagen binding

a10ß1

Collagen IV and VI

allßl

Collagen I

a3ß1

Laminin-5, Collagen IV, Fibronectin

a6ß1

Laminin-1, Merosis, Kalinin

Laminin-1 and -2

Laminin binding

a7ß1

a6ß4

Laminin-1, -2, -5 and -10

a4ß1

Fibronectin, VCAM

a5ß1

Fibronectin

a8ß1

Fibronectin

a9ß1

Fibronectin, Tenascin, Laminin-1

avßl

Fibronectin, Vitronectin

RGD motif binding

avß3

Fibronectin, Vitronectin

avß5

Vitronectin

avß6

Fibronectin

avß8

Fibronectin, Collagen IV, Laminin-5

aiibß3

Fibronectin, Vitronectin

a4ß7

Fibronectin, VCAM

aEß7

E-cadherin

aDß7

ICAM3, VCAM

ICAM1-5

Leukocyte binding

aLß2

aMß2

ICAM1, VCAM, fibrinogen

aXß2

Fibrinogen

Table 1. List of integrins and their ligands

Table 1. List of integrins and their ligands

As an integrin binds to its ligand, it undergoes structural changes which affect the ligand binding affinity [9]. This affinity is also determined by the cytoplasmic signals from within the cell which affects the molecular interactions at the integrin cytoplasmic domain influencing the degree of cell adhesion. This is refered to as inside-out signaling. Integrins also play a role in signal transduction where they transduce extracellular signals to the interior of the cell, refered to as outside-in signaling. Such signalling can affect cell migration, differentiation, survival and proliferation [10-12]. When bound to the ECM proteins, integrins recruit a range of adaptor proteins, and activate various signalling pathways. For example, integrin clustering activates the focal adhesion kinases (FAK), Src family kinases, Rac and Rho GTPases leading to the recruitment of cytoskeleton proteins such as talin, a-actinin, vincu-lin, paxillin and tensin [13]. Activation of these kinase pathways and cytoskeleton proteins contributes to changes in cell architecture, adhesion and migration on the ECM [14].

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