Role of the β3 Integrin Subunit in Human Primary Melanoma Progression: Multifunctional Activities Associated with αvβ3 Integrin Expression

Recent research into how cells interact with and function within their different (and sometimes dynamically changing) environments has become a primary focus of cell biology, centering on the examination of cell surface adhesion receptors, most notably the integrins. 1,2 Integrins form one family of cell adhesion receptors, which also include the immunoglobulin gene superfamily, selectins, cadherins, cartilage-link proteins, and cell mucins (which act as ligands for the selectins). All integrins are heterodimers composed of noncovalently linked α and β subunit transmembrane glycoproteins containing large extracellular domains, short transmembrane domains, and carboxy-terminal cytoplasmic domains of variable length. 1-5 There are presently 17 α subunits and eight β subunits known, which occur in just over 20 integrins identified so far. However, these numbers may belie the added complexity introduced by the alternately spliced cytoplasmic domains observed in some variants of these subunits. 1,6 The eight β subunits share approximately 40 to 80% amino acid sequence homology and are similar in size (90 to 110 kd) except for the β4 chain, which is almost twice as big because of its large intracytoplasmic domain. The β chains contain a fourfold repeat of cystein-rich segments and a highly conserved cytoplasmic domain with an Asp-X-Ser-X-Ser sequence (where X is any amino acid) associated with cation-dependent ligand binding and with the metal ion-dependent adhesion site motif. 2,7 This cytoplasmic tail region of the β subunits has been implicated both in cytoskeletal interactions and with signaling complexes. The α subunits, with molecular weights ranging between 120 and 180 kd, tend to be more heterogeneous than the β subunits. Furthermore, some α units contain light and heavy chains linked by a disulfide bridge in the extracellular domain, whereas other α subunits contain an extra segment of approximately 180 amino acids called the αA-domain 7 (or I domain) 1,2 inserted before the last five homologous repeats, which contain a cation-binding domain. This αA-domain contains a sequence homologous to the collagen-binding domains of von Willebrand factor, cartilage matrix protein, and complement proteins. Only recently has functional activity in recombinant versions of this domain permitted the opportunity to study ligand binding; the fragment αL A-domain has been shown to bind the intercellular cell adhesion molecule-2 (ICAM-2) and the fragment α1/α2 A-domain has been shown to bind to laminins. 7 All α subunits contain a sevenfold repeat of a homologous segment with the last three or four repeats containing the sequence Asp-X-Asp-X-Asp-Gly-X-X-Asp 1 (or related sequence) 2 motif. This motif is associated with the divalent cation-binding EF-handlike domains 2,7 and contributes to cation-dependent ligand binding to the integrin receptor. While divalent cations are required for receptor function they can also, depending on the nature of the cation, affect both the integrin’s affinity and specificity for ligands. 1-5,7 Some integrins also require divalent cations for their αβ subunit association. 1,8,9 In general, whereas the theoretical number of integrin heterodimers exceeds 100, the 20-plus observed integrins fall into three basic groups based on similar chain structures and/or the ability to recognize similar protein or adhesion motifs. These three groups include integrins which contain the β1, β2, and β3 or αv subunits; three αβ integrins do not fall within these groups. 1,2 Many α subunits can associate with just one of the β subunits, although some α subunits can associate with more than one β subunit. In particular, the αv subunit appears to be one of the most promiscuous of the α subunits and can associate with at least five different β subunits, including the β1 chain (see below). Although originally identified as cell adhesion molecules (both cell-extracellular matrix and cell-cell), integrins have most recently been shown to play significant roles in signal transduction events, 1-7 10-27 gene expression, 12,25,28 cell proliferation, 12,13,15,17,26,27,29 regulation of apoptosis 30-33 and anoikis, 32 invasion and metastasis, 2,10-12,21,26,29,33-37 embryogenesis, 38-41 tumor progression, 29 inflammation and immunity, 28 hemostasis, 42 and angiogenesis. 26,33,43-48 Recent studies have also identified integrins as points of entry for certain infection agents including hantaviruses, which appear to use the β3-containing integrins to gain entry into cells, 49 and Lyme disease spirochetes, whose attachment to human cells is mediated by the αvβ3 and α5β1 integrins. 50