Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway

In response to transforming growth factor β1 (TGFβ) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGFβ has been shown to increase the expression of specific αv integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGFβ1 increased both β3 integrin subunit mRNA and protein levels as well as surface expression of αvβ3 in human lung fibroblasts. TGFβ1-induced αvβ3 expression was strongly adhesion-dependent and associated with increased focal adhesion kinase and c-Src kinase phosphorylation. Inhibition of β3 integrin activation by the Arg-Gly-Asp tripeptide motif-specific disintegrin echistatin or αvβ3 blocking antibody prevented the increase in β3 but not β5 integrin expression. In addition, echistatin inhibited TGFβ1-induced p38 MAPK but not Smad3 activation. Furthermore, inhibition of the Src family kinases, but not focal adhesion kinase, completely abrogated TGFβ1-induced expression of αvβ3 and p38 MAPK phosphorylation but not β5 integrin expression and Smad3 activation. The TGFβ1-induced αvβ3 expression was blocked by pharmacologic and genetic inhibition of p38 MAPK- but not Smad2/3-, Sp1-, ERK-, phosphatidylinositol 3-kinase, and NF-κB-dependent pathways. Our results demonstrate that TGFβ1 induces αvβ3 integrin expression via a β3 integrin-, c-Src-, and p38 MAPK-dependent pathway. These data identify a novel mechanism for TGFβ1 signaling in human lung fibroblasts by which they may contribute to normal and pathological wound healing. In response to transforming growth factor β1 (TGFβ) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGFβ has been shown to increase the expression of specific αv integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGFβ1 increased both β3 integrin subunit mRNA and protein levels as well as surface expression of αvβ3 in human lung fibroblasts. TGFβ1-induced αvβ3 expression was strongly adhesion-dependent and associated with increased focal adhesion kinase and c-Src kinase phosphorylation. Inhibition of β3 integrin activation by the Arg-Gly-Asp tripeptide motif-specific disintegrin echistatin or αvβ3 blocking antibody prevented the increase in β3 but not β5 integrin expression. In addition, echistatin inhibited TGFβ1-induced p38 MAPK but not Smad3 activation. Furthermore, inhibition of the Src family kinases, but not focal adhesion kinase, completely abrogated TGFβ1-induced expression of αvβ3 and p38 MAPK phosphorylation but not β5 integrin expression and Smad3 activation. The TGFβ1-induced αvβ3 expression was blocked by pharmacologic and genetic inhibition of p38 MAPK- but not Smad2/3-, Sp1-, ERK-, phosphatidylinositol 3-kinase, and NF-κB-dependent pathways. Our results demonstrate that TGFβ1 induces αvβ3 integrin expression via a β3 integrin-, c-Src-, and p38 MAPK-dependent pathway. These data identify a novel mechanism for TGFβ1 signaling in human lung fibroblasts by which they may contribute to normal and pathological wound healing. One of the key events in wound repair is the infiltration of fibroblasts from surrounding tissue to the extracellular matrix (ECM) 2The abbreviations used are: ECM, extracellular matrix; TGFβ1, transforming growth factor β1; FAK, focal adhesion kinase; FRNK, FAK-related non-kinase; GFP, green fluorescent protein; SFK, Src family kinase; EGF, epidermal growth factor; RGD, Arg-Gly-Asp tripeptide motif; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; PDTC, pyrrolidine dithiocarbamate; mAb, monoclonal antibody; siRNA, short interfering RNA; Ab, antibody; FN, fibronectin; WB, Western blot; FBS, fetal bovine serum; PBS, phosphate-buffered saline; MFI, mean fluorescence intensity. in which they proliferate and differentiate into myofibroblasts. Under normal conditions myofibroblasts play a crucial role in ECM deposition and subsequent wound contraction and then disappear as the fibrotic response diminishes and normal structure and function are achieved (1Hinz B. Phan S.H. Thannickal V.J. Galli A. Bochaton-Piallat M.L. Gabbiani G. Am. J. Pathol. 2007; 170: 1807-1816Abstract Full Text Full Text PDF PubMed Scopus (1629) Google Scholar). However, their retention, uncontrolled proliferation, and excessive synthesis of ECM proteins represents a pathologic process that ultimately results in fibrosis (2Paine III, R. Ward P.A. Am. J. Med. 1999; 107: 268-279Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Both fibroblast proliferation and differentiation, as well as ECM protein synthesis, are profoundly influenced by growth factors such as TGFβ as well as cell adhesion (3Scaffidi A.K. Moodley Y.P. Weichselbaum M. Thompson P.J. Knight D.A. J. Cell Sci. 2001; 114: 3507-3516Crossref PubMed Google Scholar, 4Scaffidi A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 5Schoppet M. Chavakis T. Al-Fakhri N. Kanse S.M. Preissner K.T. Lab. Investig. 2002; 82: 37-46Crossref PubMed Scopus (47) Google Scholar, 6Thannickal V.J. Lee D.Y. White E.S. Cui Z. Larios J.M. Chacon R. Horowitz J.C. Day R.M. Thomas P.E. J. Biol. Chem. 2003; 278: 12384-12389Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar). Adhesion of cells to ECM is mediated by a family of transmembrane proteins known as integrins that are expressed on the cell surface as α/β heterodimers (7Hynes R.O. Cell. 2002; 110: 673-687Abstract Full Text Full Text PDF PubMed Scopus (6955) Google Scholar, 8Sheppard D. Physiol. Rev. 2003; 83: 673-686Crossref PubMed Scopus (123) Google Scholar). Importantly, integrins not only support cell attachment but also act in concert with receptors for several growth factors, including TGFβ, to regulate survival, migration, proliferation, and differentiation of fibroblastic, epithelial, and endothelial cells (reviewed in Refs. 7Hynes R.O. Cell. 2002; 110: 673-687Abstract Full Text Full Text PDF PubMed Scopus (6955) Google Scholar, 8Sheppard D. Physiol. Rev. 2003; 83: 673-686Crossref PubMed Scopus (123) Google Scholar). Over the past few years a close relationship between αv integrins (recognizing RGD motif) and TGFβ signaling pathways has been identified (9Yang Z. Mu Z. Dabovic B. Jurukovski V. Yu D. Sung J. Xiong X. Munger J.S. J. Cell Biol. 2007; 176: 787-793Crossref PubMed Scopus (254) Google Scholar). These include activation of latent TGFβ complexes by αvβ6 and αvβ8 integrins in airway epithelium (8Sheppard D. Physiol. Rev. 2003; 83: 673-686Crossref PubMed Scopus (123) Google Scholar, 10Munger J.S. Huang X. Kawakatsu H. Griffiths M.J. Dalton S.L. Wu J. Pittet J.F. Kaminski N. Garat C. Matthay M.A. Rifkin D.B. Sheppard D. Cell. 1999; 96: 319-328Abstract Full Text Full Text PDF PubMed Scopus (1667) Google Scholar), augmented TGFβ signaling by αvβ3 and αvβ5 integrins in scleroderma fibroblasts (11Asano Y. Ihn H. Yamane K. Jinnin M. Mimura Y. Tamaki K. J. Immunol. 2005; 175: 7708-7718Crossref PubMed Scopus (195) Google Scholar), and TGFβ receptor integrin proliferation and differentiation of human lung fibroblasts A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). also identified several as of αv integrin expression in tissue J. Cell. Full Text PDF PubMed Scopus Google Scholar, X. R. S.L. S.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was also that growth factors are to integrins and that this activation mechanism for a growth factor to a of G. G. C. R. J. Cell Biol. PubMed Scopus Google Scholar, N. Thomas K.A. A. Cell. Full Text Full Text PDF PubMed Google Scholar, H. J. 2005; PubMed Scopus Google Scholar). we that TGFβ1 not only with αvβ3 integrins but also induces their in human lung fibroblasts A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). However, the mechanisms in this process are unknown. this study was to the signaling mechanisms that αvβ3 in response to TGFβ1 The results of this study demonstrate that of β3 integrin expression not or factors, but is mediated by and specific activation of the integrin and c-Src and p38 MAPK pathways. and was by of Western and the was by of The and by M. The the Src and from and the β3 disintegrin echistatin from Src from and the pyrrolidine from Cell human lung fibroblasts from the and in with and they to the cells in and in for cells to and with human TGFβ1 or epidermal growth factor in conditions for the signaling cells with of specific signaling for to the of cells and surface expression of integrins was to for in with also to antibody then with for on Cell surface expression of αvβ3 integrin was αvβ3 integrin antibody and normal as by with fluorescence was by a and and for cells well in tissue for to The cells with of for to the of function was by Western of expression in cells and into cells by as by the cells with and with TGFβ1 for was by The expression and into lung fibroblasts to the The of to was to for cells of was by for p38 MAPK expression and by fluorescence for not cells with in for and then with for the was and cells for in the or of protein and and cells as 2002; PubMed Scopus Google Scholar). that a of of and cell strongly the expression of proteins and fibroblast of cells by of not with and cells in the of for then for and with TGFβ1 for the Western TGFβ1 stimulation, or cell signaling cell in protein with and of protein by to and with a of p38 MAPK phosphorylation was human p38 MAPK and human p38 MAPK from Cell phosphorylation was human and of human c-Src and Smad3 phosphorylation was c-Src and and to protein of β3 integrin β5 integrin and was with or human β3 human β5 integrin and was with and and and the the of the was with The results are expressed as a protein or are expressed as mean of with they TGFβ1 β3 and Cell of αvβ3 on we that TGFβ1 increased β3 mRNA expression A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). with the increased β3 fibroblasts also increased β3 subunit and αvβ3 integrin expression on the cell surface to TGFβ1 a of and in β3 protein levels increased of to TGFβ1 a of shown in surface expression of αvβ3 was also cell with TGFβ1 increase in and increase in the of integrin expression on the cell surface was for to the of expression was not from that not In not modify β3 protein or surface expression of αvβ3 of and was with TGFβ1, abrogated both TGFβ1-induced β3 subunit and αvβ3 cell surface expression and In we the of TGFβ1 on αv the β5 that of with TGFβ1 for expression of αvβ5 by β5 protein to the on αvβ3 expression. In addition, both of TGFβ1 and of TGFβ with a blocking antibody the of TGFβ1 on β3 and β5 integrin expression These results demonstrate that the TGFβ1 on αvβ3 and αvβ5 integrin expression are: associated with of integrin and specific and not mediated by a TGFβ1-induced of αvβ3 by and we shown that both and p38 MAPK in human lung fibroblasts of TGFβ1 stimulation, and activation was J.C. Lee D.Y. M. Thomas P.E. H. Cui Z. Thannickal V.J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). In we that both TGFβ1-induced Smad3 and p38 MAPK phosphorylation was and with the increased levels of β3 and β5 integrins and used to the role of signaling in the of TGFβ1 on integrin expression. In the of a was Although is with the human the of this on TGFβ1-induced expression TGFβ1-induced increase in expression in fibroblasts was completely by that the protein is in human fibroblasts However, of the not the of TGFβ1 on αvβ3 expression that TGFβ1 on β3 integrin expression is fibroblasts with or Smad3 siRNA, and the of β3 and β5 integrin expression was by The that and Smad3 protein was by with In with the results from inhibition of Smad3 not the expression of β3 integrin by In Smad3 β5 integrin expression by TGFβ1 between the proteins and the factor may a mechanism for TGFβ1 of several including integrins X. R. S.L. S.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. C. S.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to was in the of αvβ3 integrin by shown in the on β3 but prevented the increase in expression by results that the not play a role in TGFβ1-induced of αvβ3 integrins on human lung fibroblasts. TGFβ1-induced β3 Cell Adhesion and by with ECM that several in human lung fibroblasts are and (3Scaffidi A.K. Moodley Y.P. Weichselbaum M. Thompson P.J. Knight D.A. J. Cell Sci. 2001; 114: 3507-3516Crossref PubMed Google Scholar, 4Scaffidi A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 6Thannickal V.J. Lee D.Y. White E.S. Cui Z. Larios J.M. Chacon R. Horowitz J.C. Day R.M. Thomas P.E. J. Biol. Chem. 2003; 278: 12384-12389Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar). In we that TGFβ1 was to increase αvβ3 integrin expression in cells in but in cells on a surface not we integrin activation adhesion to ECM proteins the of TGFβ1 to αvβ3 expression. that cell adhesion to or not modify β3 strongly the of These that mediated by integrin activation cell adhesion are for TGFβ1 to β3 integrin expression. TGFβ1-induced β3 on αvβ3 the role of integrin activation on αvβ3 we fibroblasts with the disintegrin which has been shown to the activation of integrins in several cell H. J. 2005; PubMed Scopus Google Scholar, R. C. C. M.A. N. J. PubMed Scopus Google Scholar, C. M.A. PubMed Google Scholar). on cell attachment but the of fibroblasts to and support shown in of cells to echistatin abrogated the of TGFβ1 on but not on β5 integrin expression. that echistatin activation of αvβ3 and we levels of and phosphorylation to the inhibited TGFβ1-induced c-Src kinase and phosphorylation not in a demonstrate that echistatin β3 integrin expression by blocking but not TGFβ1 expression in response to TGFβ1 was In to expression by TGFβ1 was in the of echistatin that TGFβ1 β3 integrin expression by activation of the integrin on the cell surface of ECM proteins. also on Smad3 activation but inhibited TGFβ1-induced p38 MAPK in with β3 integrin expression and echistatin may also RGD integrins from we to the of the integrin in TGFβ1-induced β3 expression. we fibroblasts with monoclonal blocking to human αvβ3 integrin and αvβ5 integrin of to the with but not or completely abrogated the of TGFβ1 on β3 integrin expression These results support for the that the of TGFβ1 on β3 subunit expression is on the activation of but not αvβ5 on the cell surface and of protein kinases, including and c-Src of TGFβ1-induced but αvβ3 on the that integrin activation and results in activation of FAK, we the of TGFβ1 on phosphorylation. that TGFβ1 phosphorylation of on The phosphorylation of was TGFβ1 and increased with the of β3 expression. activation was in TGFβ1-induced αvβ3 fibroblasts by a a protein and to is the of and as a of A. T. PubMed Scopus Google Scholar, D. Cell Biol. PubMed Scopus Google Scholar). Western for expression in cells but not in and of fibroblasts with completely abrogated and TGFβ1-induced phosphorylation However, TGFβ1 cell surface expression of αvβ3 in both and cells and These data that inhibition of on not TGFβ1-induced αvβ3 expression. Inhibition of c-Src TGFβ1-induced αvβ3 the of c-Src kinase in TGFβ1-induced αvβ3 integrin we cells to the Src kinase and αvβ3 expression TGFβ1 shown in of cells to completely abrogated the of TGFβ1 on αvβ3 surface expression. Furthermore, with the of TGFβ1 on β3 expression a has been that Src regulate adhesion as well as signaling events by kinase but not the completely inhibited both and phosphorylation by TGFβ1 not TGFβ1-induced β3 protein increase was also strongly inhibited by but not has been that also TGFβ receptor and kinase M. Y. M.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). we also the specific which not TGFβ receptor shown in inhibited TGFβ1-induced β3 protein in a inhibited TGFβ1-induced p38 MAPK activation but not Smad3 phosphorylation These results support a role for integrin signaling in TGFβ1-induced β3 expression and that c-Src kinase and p38 MAPK but not is a key in the p38 MAPK Inhibition TGFβ1-induced αvβ3 TGFβ1 signaling including MAPK and pathways (reviewed in R. 2003; PubMed Scopus Google Scholar). Importantly, Src with pathways or and results demonstrate that p38 MAPK activation by TGFβ1 is on integrin activation and we inhibition of MAPK, including p38 and and TGFβ1-induced αvβ3 integrin expression. in in the cell surface expression of αvβ3 integrin with the the PDTC, and the for TGFβ1-induced β3 protein not However, the p38 MAPK and the a of and β3 subunit and αvβ3 integrin expression by TGFβ1 and the role of p38 MAPK, we a kinase p38 MAPK in fibroblasts K. C. S.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). increased of p38 MAPK protein was in cells but not in cells with in TGFβ1 to β3 integrin expression in Importantly, the signaling was completely and TGFβ1 β5 integrin expression in cells and of p38 MAPK phosphorylation by with not β3 integrin in cells not TGFβ1-induced p38 MAPK not of β5 but inhibited β3 protein and αvβ3 cell surface expression. Adhesion of fibroblasts to the ECM via specific integrins cell to growth factors, including TGFβ (3Scaffidi A.K. Moodley Y.P. Weichselbaum M. Thompson P.J. Knight D.A. J. Cell Sci. 2001; 114: 3507-3516Crossref PubMed Google Scholar, 4Scaffidi A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 5Schoppet M. Chavakis T. Al-Fakhri N. Kanse S.M. Preissner K.T. Lab. Investig. 2002; 82: 37-46Crossref PubMed Scopus (47) Google Scholar, 6Thannickal V.J. Lee D.Y. White E.S. Cui Z. Larios J.M. Chacon R. Horowitz J.C. Day R.M. Thomas P.E. J. Biol. Chem. 2003; 278: 12384-12389Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar), which are in and may specific a to several pathological and of the cells in the of fibrotic (2Paine III, R. Ward P.A. Am. J. Med. 1999; 107: 268-279Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, Y. Ihn H. Yamane K. Jinnin M. Mimura Y. Tamaki K. J. Immunol. 2005; 175: 7708-7718Crossref PubMed Scopus (195) Google Scholar). In this we demonstrate that TGFβ1 β3 integrin expression and subsequent αvβ3 surface expression on human lung fibroblasts via and p38 MAPK-dependent this is of the signaling pathway. the was on cell adhesion and was by TGFβ1, activation not the of TGFβ1 on αvβ3 expression. that the of TGFβ1 is on cell adhesion and activation of c-Src kinase and p38 MAPK pathway. of c-Src also completely abrogated the of TGFβ1 on activation of p38 MAPK, that c-Src is of this signaling been several the of TGFβ1 in expression and function of αvβ3 integrins on cell TGFβ1 has been shown to on αvβ3 expression in human airway cells A. Y. R. J. Sheppard D. Am. J. Cell Biol. PubMed Scopus Google Scholar). In in human cells G. J. Cell. Physiol. PubMed Scopus Google Scholar), human fibroblasts J. Cell. Full Text PDF PubMed Scopus Google Scholar), and a of cell TGFβ1 αvβ3 expression. 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However, in this study inhibition of and pathways not the of αvβ3 by In blocking of p38 MAPK activation by or of a TGFβ1-induced β3 and αvβ3 surface expression. Furthermore, we that p38 MAPK phosphorylation by TGFβ1 also inhibited by blocking of c-Src activation. the process of this and 2007; PubMed Scopus Google that c-Src on the receptor and by that TGFβ of p38 MAPK signaling in of to the mechanisms in human fibroblasts are of p38 MAPK phosphorylation in fibroblasts. study for the of and p38 signaling by TGFβ in human lung fibroblasts that may a fibrotic process in the lung or between integrins and growth factor receptors (reviewed in Refs. 7Hynes R.O. Cell. 2002; 110: 673-687Abstract Full Text Full Text PDF PubMed Scopus (6955) Google Scholar, D.A. Rev. Cell Biol. 2005; PubMed Scopus Google Scholar). we that with but not with αvβ5 integrins in human lung and this results in in TGFβ1-induced proliferation A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). However, TGFβ1 the or of αvβ3 integrins and their pathways is unknown. is that the activation of growth factor receptors by their specific has function in the signaling pathways associated with the attachment of integrins to endothelial growth factor is to the of and αvβ3 integrins in human endothelial cells N. Thomas K.A. A. Cell. Full Text Full Text PDF PubMed Google Scholar). In addition, growth factor or activation of integrins was as between growth factor receptor and integrin signaling pathways D. Cell Biol. PubMed Scopus Google Scholar). In with we that TGFβ1 of αv integrins on lung fibroblasts to their and also activation has been associated with integrin is and of focal integrin and as a between growth factor receptors and integrin D. Cell Biol. PubMed Scopus Google Scholar). 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Biol. 2002; PubMed Scopus Google Scholar), in their These results that activation of c-Src kinase, but not is the in TGFβ1-induced αvβ3 expression. has been shown that Src with αvβ3 and is integrin C. Cell. Biol. 2002; PubMed Scopus Google Scholar, H. J. S.L. J. Cell Biol. 2007; 176: PubMed Scopus Google Scholar). the of the β3 but not integrins, with Src kinase the C. Cell. Biol. 2002; PubMed Scopus Google Scholar, H. J. S.L. J. Cell Biol. 2007; 176: PubMed Scopus Google Scholar, J.S. Sci. A. 2003; PubMed Scopus Google Scholar). These may the of αvβ3 integrins for TGFβ1-induced β3 subunit expression in human lung fibroblasts. data demonstrate that disintegrin or monoclonal of αvβ3 activation not to TGFβ1 stimulation, abrogated the of both c-Src activation and β3 integrin expression. then TGFβ1 or activation and signaling of αvβ3 Our data a process of signaling or with the β3 which in induces a in the integrin in activation of the A.K. Petrovic N. Moodley Y.P. Fogel-Petrovic M. Kroeger K.M. Seeber R.M. Eidne K.A. Thompson P.J. Knight D.A. J. Biol. Chem. 2004; 279: 37726-37733Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 2007; PubMed Scopus Google Scholar). process of activation of αvβ3 integrin by of growth factor receptor in the cell has been H. J. 2005; PubMed Scopus Google Scholar). TGFβ1 also synthesis of several αvβ3 including FN, and (3Scaffidi A.K. Moodley Y.P. Weichselbaum M. Thompson P.J. Knight D.A. J. Cell Sci. 2001; 114: 3507-3516Crossref PubMed Google Scholar, J. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Ihn H. Y. Yamane K. M. Tamaki K. 2004; PubMed Scopus Google Scholar), and by of we that of fibroblasts on the of β3 subunit expression. However, ECM proteins not or β3 expression in the of Furthermore, inhibition of by not TGFβ1-induced expression of the β3 TGFβ1-induced activation of αvβ3 integrin by the expression of the αv that TGFβ1-induced expression of both β3 and β5 subunit is to the cell surface of αvβ3 and is with the that the αv subunit is and expressed in the of fibroblasts as a and the cell surface expression of integrins is by the levels of which are in the signaling mechanisms (11Asano Y. Ihn H. Yamane K. Jinnin M. Mimura Y. Tamaki K. J. Immunol. 2005; 175: 7708-7718Crossref PubMed Scopus (195) Google Scholar, D. A. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). that TGFβ1 β3 expression in a is the of factors by is a well known and of integrins N. Thomas K.A. A. Cell. Full Text Full Text PDF PubMed Google Scholar, D. Cell Biol. PubMed Scopus Google Scholar, D. H. A. M. M. Cell. Biol. 2001; PubMed Scopus Google Scholar). However, in this a not αvβ3 or in with TGFβ with blocking and of a short completely abrogated β3 integrin expression that activation of signaling as well as of TGFβ is on the by data also that the on αvβ3 expression is specific for In results a TGFβ1 induces activation of αvβ3 which in to c-Src phosphorylation and the of p38 MAPK signaling that is for β3 expression Our study for the a mechanism for the of the integrin β3 subunit expression in human which TGFβ1 and the αvβ3 integrin this to a Our data support the of a between signaling pathways and adhesion in normal wound and pathological such as M. for the of for the for and for with

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