Alpha V integrin subunit
(ITGAV)

CD51
Vitronectin receptor, alpha polypeptide
Vitronectin receptor, alpha subunit (VNRA)

Integrins are the major family of cell surface receptors mediating cell adhesion to, and migration on, extracellular matrix. Through their interactions, they modulate cytoskeletal organization as well as cell proliferation, survival, and differentiation. They are intimately involved in the regulation of embryonic development, programmed cell death, hemostasis, leukocyte homing and activation, bone resorption, clot retraction. Some of these integrins increasingly appear to play a significant role in tumor cell growth and metastasis (Clark E.A. and Brugge J.S., 1995).
Integrins are heterodimers composed of alpha and beta transmembrane subunits selected from at least 16 alpha and 8 beta subunits that heterodimerize (noncovalently) to produce more than 20 different receptors. Their ligands cross-link or cluster integrins by binding to adjacent integrin molecules on the cell surface. Integrin engagement and clustering leads to the formation of focal adhesions (FA) where integrins link to intracellular cytoskeletal complexes and bundles of actin filaments. Integrin beta subunits cytoplasmic domains are necessary and sufficient to target integrins to FA in a ligand-independent manner, whereas the alpha subunits cytoplasmic domains regulate the specificity of the ligand-dependent interactions.
Integrins-mediated signal transduction is very complex and involves protein phosphorylations (action of tyrosine kinases)(Clark E.A. and Brugge J.S., 1995).

Gene: ITGAV maps to 2q31-q32.
mRNA: size: 7 kb (main transcript).
Protein: Alpha-V integrins comprise a subset sharing a common alpha-V subunit combined with 1 of 5 beta subunits (beta-1, -3, -5, -6, or -8). All or most alpha-V integrins recognize the sequence RGD in a variety of ligands (vitronectin, fibronectin, osteopontin, bone sialoprotein, thrombospondin, fibrinogen, von Willebrand factor, tenascin, and agrin) and, in the case of alpha-V-8, laminin and type IV collagen. The vitronectin receptor consists of 2 major subunits: a 150-kD alpha subunit and a 115-kD beta subunit. The structural and functional similarities of the vitronectin receptor, the fibronectin receptor, and the gpIIb/IIIa glycoprotein of platelets suggest that they are homologous membrane proteins with a common evolutionary origin.

Cell lines:
- The expression and function of alpha_V integrins was characterized in three breast cancer cell (BCC) lines which exhibit different metastatic potentials. These included MCF-7 cells which metastasize inefficiently, MDA-MB-231 cells, which have a moderate metastatic potential, and MDA-MB-435 cells, which metastasize extensively. Each cell type displayed a different repertoire of alpha_V integrins on the cell surface. The complement of alpha_V integrins on each cell type influenced their ability to adhere and migrate. The most striking difference among these cell lines was the expression of the alpha_Vbeta₃ integrin. The highly metastatic MDA-MB-435 cells expressed substantial levels of this receptor, whereas MDA-MB-231 and MCF-7 cells did not. The MDA-MB-435 cells showed a greater ability to adhere and to migrate and this functional difference could be due to the expression of alpha_Vbeta₃ integrin (Wong N.C. et al., 1998).

- Recombinant maspin (rMaspin) was shown to induce higher cell surface levels of alpha₅- and alpha₃-containing integrins and reduced levels of alpha₂-, alpha₄-, alpha₆-, alpha_V-, and some beta₁-containing integrins in the metastatic BCC line MDA-MB-435 concomitant with its ability to inhibit the invasive process in vitro (Seftor R.E. et al., 1998).

- Purified bone sialoprotein (BSP), recombinant human BSP fragments and BSP-derived RGD peptides were shown to elicit migratory, adhesive, and proliferative responses in the MDA-MB-231 BCC line. Experiments with integrin-blocking antibodies demonstrated that BSP-RGD-induced migration utilizes the alpha_Vbeta₃ vitronectin receptor, whereas adhesion and proliferation responses were alpha_Vbeta₅-mediated (Sung V. et al., 1998).

- The phenotypic characteristics of 2 tumor cell lines (BC-H1 and BC-K1) established from bone marrow of patients with breast cancer were studied by immunocytochemistry, flow cytometry, and RT-PCR. Both cell lines expressed E-cadherin, vimentin, cytokeratins (including component 18), alpha 5-, alpha V-, beta 1-, and beta 3- integrin subunits, ICAM-1, MCAM, LFA-3 (CD58), and CD44s (but not CD44v5, v6, v7/8). BC-H1 also expressed ErbB2 (not found in BC-K1), and MAGE-4 (but not MAGE-1, -2, -3/6, -12; BC-K1 was not tested). The expressed molecules might be potential candidates for novel therapeutic targets (Putz E. et al., 1999).

- MCF-7 BCC were shown to exhibit a urokinase-dependent physical association between uPAR and the vitronectin receptor alpha_Vbeta₅. These BCC responded to urokinase or to its noncatalytic amino-terminal fragment by exhibiting remarkable cytoskeletal rearrangements that were mediated by alpha_Vbeta₅ and required protein kinase C activity. On the contrary, binding of vitronectin to alpha_Vbeta₅ resulted in the protein kinase C-independent formation of F-actin containing microspike-type structures. Furthermore, alpha_Vbeta₅ was required for urokinase-directed, receptor-dependent MCF-7 BCC migration (Carriero M.V. et al., 1999).

Tumors:
- Alpha-V integrins have been proposed as targets for the inhibition of tumor angiogenesis. However, it has been found that ablation of the gene for the alpha-V integrin subunit, although causing lethality, allows considerable development and organogenesis including, most notably, extensive vasculogenesis and angiogenesis. (Bader B.L. et al., 1998) . These results necessitate reevaluation of the primacy of alpha-V integrins in many functions including vascular development, despite reports that blockade of these integrins with antibodies or peptides prevents angiogenesis.

- In a series of 197 consecutive patients with invasive breast cancer and long follow-up, vascular expression of integrin alpha_Vbeta₃ in tumor vascular ''hot spots'' was found to be the most significant prognostic factor predictive of relapse-free survival in both node-negative and node-positive patients (Gasparini G. et al., 1998).

- Studies have indicated that uPAR could be associated in large molecular complexes with other molecules, such as integrins. In a study of 10 human breast carcinomas, the ability of uPAR to physically associate with the vitronectin receptor alpha_Vbeta₅ was shown (Carriero M.V. et al., 1999).

Bader B.L. et al. (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha-V integrins. Cell 95, 507-519.
Carriero M.V. et al. (1999) Urokinase receptor interacts with alpha(v)beta5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer. Cancer Res. 59, 5307-5314.
Clark E.A. and Brugge J.S. (1995) Integrins and signal transduction pathways: the road taken. Science 268, 233-239 (Review).
Fernandez-Ruiz E. et al. (1993) Regional localization of the human vitronectin receptor alpha-subunit gene (VNRA) to chromosome 2q31-q32. Cytogenet. Cell Genet. 62, 26-28.
Gasparini G. et al. (1998) Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. Clin. Cancer Res. 4, 2625-2634.
Liapis H. et al. (1996) Integrin alpha_Vbeta₃ expression by bone-residing breast cancer metastases. Diagn. Mol. Pathol. 5, 127-135.
Putz E. et al. (1999) Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res. 59, 241-248.
Seftor R.E. et al. (1998) Maspin suppresses the invasive phenotype of human breast carcinoma. Cancer Res. 58, 5681-5685.
Sung V. et al. (1998) Bone sialoprotein supports breast cancer cell adhesion proliferation and migration through differential usage of the alpha(v)beta3 and alpha(v)beta5 integrins. J. Cell Physiol. 176, 482-494.
Suzuki, S. et al.(1986) cDNA and amino acid sequences of the cell adhesion protein receptor recognizing vitronectin reveal a transmembrane domain and homologies with other adhesion protein receptors. Proc. Nat. Acad. Sci. 83, 8614-8618.
van der Pluijm G. et al (1997) Attachment characteristics and involvement of integrins in adhesion of breast cancer cell lines to extracellular bone matrix components. Lab. Invest. 77, 665-675.
Wong N.C. et al. (1998) Alphav integrins mediate adhesion and migration of breast carcinoma cell lines. Clin. Exp. Metastasis 16, 50-61.

About integrins, Beta 1, beta 3, beta 5