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Proc Natl Acad Sci U S A. Oct 1, 1991; 88(19): 8392–8396.

Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins.


The integrin family of cell adhesion receptors mediates many of the interactions between cells and the extracellular matrix. Because the extracellular matrix has profound influences on cell behavior, it seems likely that integrins transduce biochemical signals across the cell membrane. The nature of these putative signals has, thus far, remained elusive. Antibody-mediated clustering of integrin receptors was used to mimic the integrin clustering process that occurs during formation of adhesive contacts. Human epidermal carcinoma (KB) cells were incubated with an anti-beta 1 integrin monoclonal antibody for 30 min on ice followed by incubation at 37 degrees C with anti-rat IgG. This treatment, which induced integrin clustering, stimulated the phosphorylation on tyrosine residues of a 115- to 130-kDa complex of proteins termed pp130. When integrins were clustered in the presence of the phosphatase inhibitor sodium orthovanadate, pp130 showed a substantial increase in phosphorylation compared to the case in which integrins were clustered in the absence of vanadate. Maximal pp130 phosphorylation was observed 10-20 min after initiation of integrin clustering in the absence of vanadate or after 5-10 min in its presence. These time courses roughly parallel the formation of integrin clusters on the cell surface as observed by fluorescence microscopy. pp130 phosphorylation depended on the amount of anti-integrin antibody present. Additionally, the tyrosine phosphorylation of pp130 showed specificity since it was stimulated by antibodies to the integrin alpha 3 and beta 1 subunits but not by antibodies to other integrin alpha subunits or to nonintegrin cell surface proteins. Immunoprecipitation experiments clearly demonstrated that pp130 is not itself a beta 1 integrin. It is postulated, therefore, that the integrin-stimulated tyrosine phosphorylation of pp130 may reflect part of an important signal transduction process between the extracellular matrix and the cell interior.

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  • McClay DR, Ettensohn CA. Cell adhesion in morphogenesis. Annu Rev Cell Biol. 1987;3:319–345. [PubMed]
  • Sanes JR. Extracellular matrix molecules that influence neural development. Annu Rev Neurosci. 1989;12:491–516. [PubMed]
  • Ben-Ze'ev A, Robinson GS, Bucher NL, Farmer SR. Cell-cell and cell-matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2161–2165. [PMC free article] [PubMed]
  • Streuli CH, Bissell MJ. Expression of extracellular matrix components is regulated by substratum. J Cell Biol. 1990 Apr;110(4):1405–1415. [PMC free article] [PubMed]
  • Brown PJ, Juliano RL. Selective inhibition of fibronectin-mediated cell adhesion by monoclonal antibodies to a cell-surface glycoprotein. Science. 1985 Jun 21;228(4706):1448–1451. [PubMed]
  • Hynes RO. Integrins: a family of cell surface receptors. Cell. 1987 Feb 27;48(4):549–554. [PubMed]
  • Juliano RL. Membrane receptors for extracellular matrix macromolecules: relationship to cell adhesion and tumor metastasis. Biochim Biophys Acta. 1987 Nov 25;907(3):261–278. [PubMed]
  • Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science. 1987 Oct 23;238(4826):491–497. [PubMed]
  • Buck CA, Horwitz AF. Cell surface receptors for extracellular matrix molecules. Annu Rev Cell Biol. 1987;3:179–205. [PubMed]
  • McDonald JA. Receptors for extracellular matrix components. Am J Physiol. 1989 Dec;257(6 Pt 1):L331–L337. [PubMed]
  • Akiyama SK, Nagata K, Yamada KM. Cell surface receptors for extracellular matrix components. Biochim Biophys Acta. 1990 Feb 28;1031(1):91–110. [PubMed]
  • Hemler ME. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365–400. [PubMed]
  • Otey CA, Pavalko FM, Burridge K. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J Cell Biol. 1990 Aug;111(2):721–729. [PMC free article] [PubMed]
  • Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol. 1988;4:487–525. [PubMed]
  • Chen WT, Hasegawa E, Hasegawa T, Weinstock C, Yamada KM. Development of cell surface linkage complexes in cultured fibroblasts. J Cell Biol. 1985 Apr;100(4):1103–1114. [PMC free article] [PubMed]
  • Damsky CH, Knudsen KA, Bradley D, Buck CA, Horwitz AF. Distribution of the cell substratum attachment (CSAT) antigen on myogenic and fibroblastic cells in culture. J Cell Biol. 1985 May;100(5):1528–1539. [PMC free article] [PubMed]
  • Lark MW, Laterra J, Culp LA. Close and focal contact adhesions of fibroblasts to a fibronectin-containing matrix. Fed Proc. 1985 Feb;44(2):394–403. [PubMed]
  • Schreiner CL, Bauer JS, Danilov YN, Hussein S, Sczekan MM, Juliano RL. Isolation and characterization of Chinese hamster ovary cell variants deficient in the expression of fibronectin receptor. J Cell Biol. 1989 Dec;109(6 Pt 1):3157–3167. [PMC free article] [PubMed]
  • Ingber DE, Prusty D, Frangioni JV, Cragoe EJ, Jr, Lechene C, Schwartz MA. Control of intracellular pH and growth by fibronectin in capillary endothelial cells. J Cell Biol. 1990 May;110(5):1803–1811. [PMC free article] [PubMed]
  • Matsuyama T, Yamada A, Kay J, Yamada KM, Akiyama SK, Schlossman SF, Morimoto C. Activation of CD4 cells by fibronectin and anti-CD3 antibody. A synergistic effect mediated by the VLA-5 fibronectin receptor complex. J Exp Med. 1989 Oct 1;170(4):1133–1148. [PMC free article] [PubMed]
  • Nojima Y, Humphries MJ, Mould AP, Komoriya A, Yamada KM, Schlossman SF, Morimoto C. VLA-4 mediates CD3-dependent CD4+ T cell activation via the CS1 alternatively spliced domain of fibronectin. J Exp Med. 1990 Oct 1;172(4):1185–1192. [PMC free article] [PubMed]
  • Shimizu Y, Van Seventer GA, Horgan KJ, Shaw S. Regulated expression and binding of three VLA (beta 1) integrin receptors on T cells. Nature. 1990 May 17;345(6272):250–253. [PubMed]
  • Giancotti FG, Ruoslahti E. Elevated levels of the alpha 5 beta 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell. 1990 Mar 9;60(5):849–859. [PubMed]
  • Schreiner C, Fisher M, Hussein S, Juliano RL. Increased tumorigenicity of fibronectin receptor deficient Chinese hamster ovary cell variants. Cancer Res. 1991 Mar 15;51(6):1738–1740. [PubMed]
  • Werb Z, Tremble PM, Behrendtsen O, Crowley E, Damsky CH. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol. 1989 Aug;109(2):877–889. [PMC free article] [PubMed]
  • Sporn SA, Eierman DF, Johnson CE, Morris J, Martin G, Ladner M, Haskill S. Monocyte adherence results in selective induction of novel genes sharing homology with mediators of inflammation and tissue repair. J Immunol. 1990 Jun 1;144(11):4434–4441. [PubMed]
  • McCune BK, Earp HS. The epidermal growth factor receptor tyrosine kinase in liver epithelial cells. The effect of ligand-dependent changes in cellular location. J Biol Chem. 1989 Sep 15;264(26):15501–15507. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Huckle WR, Prokop CA, Dy RC, Herman B, Earp S. Angiotensin II stimulates protein-tyrosine phosphorylation in a calcium-dependent manner. Mol Cell Biol. 1990 Dec;10(12):6290–6298. [PMC free article] [PubMed]
  • Huckle WR, Hepler JR, Rhee SG, Harden TK, Earp HS. Protein kinase C inhibits epidermal growth factor-dependent tyrosine phosphorylation of phospholipase C gamma and activation of phosphoinositide hydrolysis. Endocrinology. 1990 Oct;127(4):1697–1705. [PubMed]
  • Swarup G, Speeg KV, Jr, Cohen S, Garbers DL. Phosphotyrosyl-protein phosphatase of TCRC-2 cells. J Biol Chem. 1982 Jul 10;257(13):7298–7301. [PubMed]
  • Sczekan MM, Juliano RL. Internalization of the fibronectin receptor is a constitutive process. J Cell Physiol. 1990 Mar;142(3):574–580. [PubMed]
  • Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–478. [PubMed]
  • Streuli M, Krueger NX, Tsai AY, Saito H. A family of receptor-linked protein tyrosine phosphatases in humans and Drosophila. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8698–8702. [PMC free article] [PubMed]
  • Veillette A, Bookman MA, Horak EM, Bolen JB. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. [PubMed]
  • Samelson LE, Phillips AF, Luong ET, Klausner RD. Association of the fyn protein-tyrosine kinase with the T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4358–4362. [PMC free article] [PubMed]
  • Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K. Association of B cell antigen receptor with protein tyrosine kinase Lyn. Science. 1991 Jan 11;251(4990):192–194. [PubMed]
  • Matten WT, Aubry M, West J, Maness PF. Tubulin is phosphorylated at tyrosine by pp60c-src in nerve growth cone membranes. J Cell Biol. 1990 Nov;111(5 Pt 1):1959–1970. [PMC free article] [PubMed]
  • Kanner SB, Reynolds AB, Vines RR, Parsons JT. Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases. Proc Natl Acad Sci U S A. 1990 May;87(9):3328–3332. [PMC free article] [PubMed]
  • Bushman WA, Wilson LK, Luttrell DK, Moyers JS, Parsons SJ. Overexpression of c-src enhances beta-adrenergic-induced cAMP accumulation. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7462–7466. [PMC free article] [PubMed]
  • Golden A, Brugge JS, Shattil SJ. Role of platelet membrane glycoprotein IIb-IIIa in agonist-induced tyrosine phosphorylation of platelet proteins. J Cell Biol. 1990 Dec;111(6 Pt 2):3117–3127. [PMC free article] [PubMed]
  • Ferrell JE, Jr, Martin GS. Tyrosine-specific protein phosphorylation is regulated by glycoprotein IIb-IIIa in platelets. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2234–2238. [PMC free article] [PubMed]
  • Wayner EA, Carter WG. Identification of multiple cell adhesion receptors for collagen and fibronectin in human fibrosarcoma cells possessing unique alpha and common beta subunits. J Cell Biol. 1987 Oct;105(4):1873–1884. [PMC free article] [PubMed]
  • Sonnenberg A, Modderman PW, Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature. 1988 Dec 1;336(6198):487–489. [PubMed]

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