Alternative titles; symbols
HGNC Approved Gene Symbol: ITGA5
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:54,395,261-54,419,266 (from NCBI)
The fibronectin receptor, a member of the integrin family of heterodimeric glycopeptides, mediates binding of cells to fibronectin substrata. To study the structure of the receptor, Argraves et al. (1986) isolated cDNA clones coding for the alpha subunit from a placenta cDNA library. The cDNAs code for 229 amino acids from the C terminus of the alpha subunit. The deduced sequence has a hydrophobic region with properties characteristic of a membrane-spanning domain. Argraves et al. (1987) deduced the amino acid sequence from cDNA. The alpha subunit, which is processed into 2 polypeptides disulfide-bonded to one another, has 1,008 amino acids; the beta subunit has 778 amino acids. Fitzgerald et al. (1987) presented comparisons of the cDNA-derived protein sequences of fibronectin receptor, vitronectin receptor (193210), and platelet glycoprotein IIb (607759).
Kwok et al. (2007) found that the Helicobacter pylori (see 600263) adhesin protein CagL was targeted to the bacterial type IV secretion pilus surface, where it bound and activated the ITGA5/ITGB1 (135630) receptor on gastric epithelial cells through its arg-gly-asp motif. CagL interaction with the integrin receptor triggered delivery of the H. pylori oncoprotein CagA into target cells and activation of FAK (PTK2; 600758) and SRC (190090) tyrosine kinases. Kwok et al. (2007) suggested that CagL may be used as a molecular tool to better understand integrin signaling and the mechanism by which H. pylori causes gastric ulcer and cancer.
Travis et al. (2007) showed that conditional loss of the TGF-beta (190180)-activating integrin alpha-V/beta-8 (604160) on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha-V/beta-8 on dendritic cells, as mice lacking alpha-V/beta-8 principally on dendritic cells develop identical immunologic abnormalities as mice lacking alpha-V/beta-8 on all leukocytes, whereas mice lacking alpha-V/beta-8 on T cells alone are phenotypically normal. Travis et al. (2007) further showed that dendritic cells lacking alpha-V/beta-8 failed to induce regulatory T cells in vitro, an effect that depends on TGF-beta activity. Furthermore, mice lacking alpha-V/beta-8 on dendritic cells had reduced proportions of regulatory T cells in colonic tissue. Travis et al. (2007) concluded that alpha-V/beta-8-mediated TGF-beta activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of alpha-V/beta-8 on dendritic cells to induce and/or maintain tissue regulatory cells.
Lammermann et al. (2008) studied the interplay between adhesive, contractile, and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro. The authors ablated genes encoding integrin heterodimeric partners ITGA5, ITGB1, ITGB2 (600065), and ITGB7 (147559) from murine leukocytes and demonstrated that functional integrins do not contribute to migration in 3-dimensional environments. Instead, these cells migrate by the sole force of actin network expansion, which promotes protrusive flowing of the leading edge. Myosin II-dependent contraction is required only on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus.
Friedland et al. (2009) showed that the alpha-5/beta-1 (135630) integrin switches between relaxed and tensioned states in response to myosin II (see 160776)-generated cytoskeletal force. Force combines with extracellular matrix stiffness to generate tension that triggers the integrin switch. This switch directly controls the alpha-5/beta-1-fibronectin bond strength through engaging the synergy site in fibronectin and is required to generate signals through phosphorylation of focal adhesion kinase. In the context of tissues, this integrin switch connects cytoskeleton and extracellular matrix mechanics to adhesion-dependent motility and signaling pathways.
Sosnoski et al. (1988) assigned the FNRA gene to chromosome 12q11-q13 by Southern analysis of somatic cell hybrid DNA. Location on chromosome 12 was confirmed by Spurr and Rooke (1991) by study of human/rodent somatic cell hybrids. Krissansen et al. (1992) pointed out the possible significance of the fact that a related gene coding for integrin beta-7 subunit (ITGB7; 147559) is also located on chromosome 12.
Adkison et al. (1994) mapped the murine homolog, Itga5, to chromosome 15, distal to D15Mit16, by analysis of DNA from an interspecific backcross.
Mouse embryos genetically null for the alpha integrin subunit develop intracerebral hemorrhages at midgestation and die shortly after birth. McCarty et al. (2002) determined that the endothelial cells and pericytes established normal cerebral microvessels, however, light and electron microscopy revealed defective associations between cerebral microvessels and the neuroepithelial cells, glia, and neuronal precursors of the surrounding brain parenchyma. McCarty et al. (2002) concluded that alpha integrins provide an association between cerebral microvessels and central nervous system parenchymal cells, and defective association leads to cerebral hemorrhage.
Adkison, L. R., White, R. A., Haney, D. M., Lee, J. C., Pusey, K. T., Gardner, J. The fibronectin receptor, alpha subunit (Itga5) maps to murine chromosome 15, distal to D15Mit16. Mammalian Genome 5: 456-457, 1994. [PubMed: 7919661] [Full Text: https://doi.org/10.1007/BF00357009]
Argraves, W. S., Pytela, R., Suzuki, S., Millan, J. L., Pierschbacher, M. D., Ruoslahti, E. cDNA sequences from the alpha subunit of the fibronectin receptor predict a transmembrane domain and a short cytoplasmic peptide. J. Biol. Chem. 261: 12922-12924, 1986. [PubMed: 2944883]
Argraves, W. S., Suzuki, S., Arai, H., Thompson, K., Pierschbacher, M. D., Ruoslahti, E. Amino acid sequence of the human fibronectin receptor. J. Cell Biol. 105: 1183-1190, 1987. [PubMed: 2958481] [Full Text: https://doi.org/10.1083/jcb.105.3.1183]
Fitzgerald, L. A., Poncz, M., Steiner, B., Rall, S. C., Jr., Bennett, J. S., Phillips, D. R. Comparison of cDNA-derived protein sequences of the human fibronectin and vitronectin receptor alpha-subunits and platelet glycoprotein IIb. Biochemistry 26: 8158-8165, 1987. [PubMed: 2450560] [Full Text: https://doi.org/10.1021/bi00399a021]
Friedland, J. C., Lee, M. H., Boettiger, D. Mechanically activated integrin switch controls alpha-5/beta-1 function. Science 323: 642-644, 2009. [PubMed: 19179533] [Full Text: https://doi.org/10.1126/science.1168441]
Krissansen, G. W., Yuan, Q., Jenkins, D., Jiang, W.-M., Rooke, L., Spurr, N. K., Eccles, M., Leung, E., Watson, J. D. Chromosomal locations of the genes coding for the integrin beta-6 and beta-7 subunits. Immunogenetics 35: 58-61, 1992. [PubMed: 1729173] [Full Text: https://doi.org/10.1007/BF00216629]
Kwok, T., Zabler, D., Urman, S., Rohde, M., Hartig, R., Wessler, S., Misselwitz, R., Berger, J., Sewald, N., Konig, W., Backert, S. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449: 862-866, 2007. [PubMed: 17943123] [Full Text: https://doi.org/10.1038/nature06187]
Lammermann, T., Bader, B. L., Monkley, S. J., Worbs, T., Wedlich-Soldner, R., Hirsch, K., Keller, M., Forster, R., Critchley, D. R., Fassler, R., Sixt, M. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453: 51-55, 2008. [PubMed: 18451854] [Full Text: https://doi.org/10.1038/nature06887]
McCarty, J. H., Monahan-Earley, R. A., Brown, L. F., Keller, M., Gerhardt, H., Rubin, K., Shani, M., Dvorak, H. F., Wolburg, H., Bader, B. L., Dvorak, A. M., Hynes, R. O. Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alpha-v integrins. Molec. Cell. Biol. 22: 7667-7677, 2002. [PubMed: 12370313] [Full Text: https://doi.org/10.1128/MCB.22.21.7667-7677.2002]
Sosnoski, D., Emanuel, B. S., Hawkins, A. L., van Tuinen, P., Ledbetter, D. H., Nussbaum, R. L., Kaos, F.-T., Schwartz, E., Phillips, D., Bennett, J. S., Fitzgerald, L. A., Poncz, M. Chromosomal localization of the genes for the vitronectin and fibronectin receptors alpha-subunits and for platelet glycoproteins IIb and IIIa. J. Clin. Invest. 81: 1993-1998, 1988. [PubMed: 2454952] [Full Text: https://doi.org/10.1172/JCI113548]
Spurr, N. K., Rooke, L. Confirmation of the assignment of the vitronectin (VNRA) and fibronectin (FNRA) receptor alpha-subunits. Ann. Hum. Genet. 55: 217-223, 1991. [PubMed: 1722386] [Full Text: https://doi.org/10.1111/j.1469-1809.1991.tb00416.x]
Travis, M. A., Reizis, B., Melton, A. C., Masteller, E., Tang, Q., Proctor, J. M., Wang, Y., Bernstein, X., Huang, X., Reichardt, L. F., Bluestone, J. A., Sheppard, D. Loss of integrin alpha-V/beta-8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449: 361-365, 2007. [PubMed: 17694047] [Full Text: https://doi.org/10.1038/nature06110]