Integrins in Ocular Angiogenesis

Abstract

The integrin family of membrane proteins are ubiquitously expressed cell surface receptors that not only mediate cell anchorage to the surrounding extracellular matrix, but are also critically important in transducing environmental cues to subcellular signaling pathways. Integrins play important roles in cell differentiation and survival and have generated interest in diverse fields ranging from structural biology and immunology to tumor biology and ophthalmology. Much of the interest has centered on the roles of integrins during cell-cell adhesion, such as that which occurs between endothelial cells and leukocytes during arrest and extravasation from blood vessels during inflammation. Another major area of interest has been the function of integrins and their interaction with the extracellular matrix (ECM). Integrins specifically bind components of the ECM such as fibronectin and vitronectin, but also non-ECM molecules such as von Willebrand factor and thrombospondin. The specificity of interaction with various ligands is a result of the noncovalently linked α/β chains that form the functional integrin heterodimer. The α-subunit is comprised of approx 1000 amino acids and contains calcium-binding motifs that are critical to integrin function (1). Integrin β-subunits are made up of approx 750 amino acids and introduce additional variability through alternative splicing of the cytoplasmic regions. Different pairings of α- and β-subunits produce at least 20 different integrin heterodimers with distinct but overlapping binding specificities (2). In turn, each ECM component may be recognized by several integrins. In general, integrins recognize amino acid sequences that contain a key acidic residue that is critical for binding (3). A common example of an integrin ligand sequence is the RGD (Arg-Gly-Asp) sequence, which is found in a number of integrin-binding proteins (4). Integrin-binding sequences that are unrelated to the RGD motif show structural and topological similarities to the RGD sequence, suggesting that specific spatial elements are required for recognition (5). Some integrins are known to require activation in order to bind their corresponding ligands, a mechanism referred to as “inside-out” signaling. For example, the α_IIbβ₃ integrin is a constitutively expressed receptor on platelets but is able to bind its primary ligand, fibrinogen, only after a conformational change induced by platelet activation (6).