Processing of Integrin αv Subunit by Membrane Type 1 Matrix Metalloproteinase Stimulates Migration of Breast Carcinoma Cells on Vitronectin and Enhances Tyrosine Phosphorylation of Focal Adhesion Kinase

Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases, MT1-MMP directly processes a single chain precursor of αvintegrin subunit (pro-αv) into the heavy and light α-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing αvβ3 integrin with either the wild type or mutant MT1-MMP in a variety of migration and adhesion tests. Specific inhibitors of proprotein convertases and MMP were employed in our cell system to attenuate the individual pathways of pro-αv maturation. We present evidence that MT1-MMP cleavage of pro-αv in the cells did not affect RGD-ligand binding of the resulting αvβ3 integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and αvβ3integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of αvβ3integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and αvβ3 integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. Regulation of integrin maturation and functionality may be an important role of MT1-MMP in tumor cells. Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases, MT1-MMP directly processes a single chain precursor of αvintegrin subunit (pro-αv) into the heavy and light α-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing αvβ3 integrin with either the wild type or mutant MT1-MMP in a variety of migration and adhesion tests. Specific inhibitors of proprotein convertases and MMP were employed in our cell system to attenuate the individual pathways of pro-αv maturation. We present evidence that MT1-MMP cleavage of pro-αv in the cells did not affect RGD-ligand binding of the resulting αvβ3 integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and αvβ3integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of αvβ3integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and αvβ3 integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. Regulation of integrin maturation and functionality may be an important role of MT1-MMP in tumor cells. matrix metalloproteinase membrane type 1 matrix metalloproteinase focal adhesion kinase phenylmethylsulfonyl fluoride Dulbecco's modified Eagle's medium fetal calf serum bovine serum albumin Dulbecco's phosphate-buffered saline horseradish peroxidase Tris-buffered saline cyclo(Arg-Gly-Asp-d-Phe-Val) peptide decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone wild type monoclonal antibody Integrins are a family of αβ-heterodimeric cell adhesion molecules consisting of two type I transmembrane glycoprotein subunits. Eight integrin β-chains pair with a restricted number of 16 α-chains, giving rise to 22 different integrins with distinct expression patterns and ligand binding profiles (1Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (9011) Google Scholar, 2Ivaska J. Heino J. Cell. Mol. Life Sci. 2000; 57: 16-24Crossref PubMed Scopus (133) Google Scholar). 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Cell Biol. 2000; PubMed Scopus Google and K. J. S. M. S.A. M. I. H. Cell. 1999; 99: Full Text Full Text PDF PubMed Scopus Google as as in the proteolytic processing of cell surface Ratnikov E.I. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. T. H. Okada A. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google Scholar). is a between the expression of MT1-MMP and in (33Hotary K. Allen E. Punturieri A. Yana I. Weiss S.J. J. Cell Biol. 2000; PubMed Scopus Google Scholar, M. 1999; PubMed Scopus Google Scholar, Mol. Biol. 2001; Google Scholar). B. T. R. G. J. E. and A. Y. Biol. Chem. we evidence that MT1-MMP is of processing the precursor of the αv integrin subunit as an integrin in breast carcinoma MCF7 cells co-expressing αvβ3integrin and MT1-MMP, the a heavy α-chain with the and a light α-chain from the N-terminal with these our (20Deryugina E.I. Bourdon M.A. Jungwirth K. Smith J.W. Strongin A.Y. Int. J. Cancer. 2000; 86: 15-23Crossref PubMed Scopus (153) Google Scholar, 21Deryugina E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google that the cells co-expressing MT1-MMP and αvβ3 integrin were to the cells with MT1-MMP or αvβ3 integrin This to the of cells in we that processing of pro-αv by MT1-MMP αvβ3 adhesion and migration of cells on vitronectin, the matrix ligand of αvβ3integrin. MT1-MMP cleavage of pro-αv did not affect RGD-ligand binding of αvβ3 the cells both αvβ3integrin and MT1-MMP were efficient in outside-in signal transduction through a focal adhesion kinase to the cells αvβ3 integrin that of integrin functionality may be an important role of MT1-MMP in migrating tumor cells. to a of MT1-MMP and were from as J.W. A. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). from of MMP J. H. S. K. Clin. Cancer Res. 1999; Google a of decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone from of inhibitors and and were from from human plasma a of DiScipio MCF7 cells and co-expressing αvβ3 integrin with the wild type or the inactive mutant in the the essential of the were E.I. Ratnikov Monosov G.N. Quigley J.P. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). MCF7 cell in αvβ3 integrin and with and (20Deryugina E.I. Bourdon M.A. Jungwirth K. Smith J.W. Strongin A.Y. Int. J. Cancer. 2000; 86: 15-23Crossref PubMed Scopus (153) Google Scholar, 21Deryugina E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google Scholar). MCF7 cells with both and (20Deryugina E.I. Bourdon M.A. Jungwirth K. Smith J.W. Strongin A.Y. Int. J. Cancer. 2000; 86: 15-23Crossref PubMed Scopus (153) Google Scholar, 21Deryugina E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google were as human cells and cells the wild type were and in our E.I. Bourdon M.A. Strongin A. Cancer Res. 1998; Google Scholar). cell were in with or both at were in with the of a with the cells were with and with to the cells were with and with in with 1 1 and 1 and of and The were with The of cell of were with of or and at were with 1 1 and and of and with with and and with were by the in were and to were to an membrane with in the membrane with and the activity with the were in with or a were with or the with with and in the with in were at with the of and with and with were to 1 to cells were with with 1 and 1 and with in 1 and and of and 1 on cell were at at The of cell of were with and at were with 1 and and of and with with and and with with were by the in were and to were to a with the membrane with or by with and the To the in the the of the and an and binding as Ratnikov Smith J.W. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). were with of at binding in the presence of from ligand by through a of in at The in in a The of the were by and by the with a single binding Cell adhesion in the of a binding at with or at the were 1 at with with were in with and in with with were at in with and to 1 at the of cyclo(Arg-Gly-Asp-d-Phe-Val) peptide were to cell cells were and with and the and E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google Scholar). The migration of cells in as E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google Scholar). The of a membrane with an at with and with in were with were in medium The with of cells that to the of the membrane were with and cells were in the presence of and into with the to both and we the mechanisms MT1-MMP in the proteolytic cleavage of pro-αv in MCF7 breast carcinoma cells. that MT1-MMP as an integrin Similar to furin-like proprotein convertases, MT1-MMP converts a single chain pro-αv into the heavy and light α-chains connected by a disulfide bridge. To these and to that the processing of pro-αv by MT1-MMP is not restricted to a single cell we examined the cell of the cells that MT1-MMP E.I. Bourdon M.A. Strongin A. Cancer Res. 1998; Google Scholar). as To attenuate the of MT1-MMP on we the of pro-αv maturation by and breast carcinoma cells with a E. A. F. H. G. 1998; PubMed Scopus (87) Google Scholar, T. T. T. Seiki M. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). with our E.I. Ratnikov Monosov G.N. Quigley J.P. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google activation of MT1-MMP is not by of in breast carcinoma and cells. with the cells were and the cell were with The the cleavage of pro-αv and the of the pro-αv chain in control cells. the of the mature heavy α-chain in both control cell types, MCF7 and with the the on the processing of pro-αv in both breast carcinoma and cells co-expressing αvβ3 integrin and these cells the to pro-αv maturation. These our and that the of is likely to in cell types, a To the functional of our we the ligand binding of αvβ3 integrin in cells these the ligand binding of αvβ3 integrin expressed in and cells a as an RGD-ligand highly integrins J.W. A. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, Smith J.W. Sci. S. A. PubMed Scopus Google Scholar). that similar to the ligand MT1-MMP-processed of αvβ3 To these we the ligand binding of to αvβ3 integrin expressed in and cells. Binding of αvβ3 integrin by and as of binding not of the were these cell in the number of in and of the binding of αvβ3integrin expressed in is the number of in is the number of in in a and cells were efficient in adhesion to of To on the of MT1-MMP on ligand binding of αvβ3 we examined the of and cells on with in the presence of of the that the peptide efficient in adhesion of all these cell to these that the processing of integrin αv subunit not affect the ligand binding of the resulting αvβ3 To evaluate the of the on cell we cell adhesion and migration on vitronectin, a ligand of αvβ3integrin. we the of cells to to of with our E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google our that in a cells were to to or cells This in adhesion of the cells at the of the all cell were highly similar in their to of the peptide that of cells to these of MT1-MMP and αvβ3 integrin cell adhesion to the binding of the we the migration of cells in with the membrane with in these we cells that are in αvβ3 integrin but the wild type To the of MT1-MMP and αvβ3 integrin expressed on cell cells were with cell MT1-MMP and αvβ3 integrin were with and by of MT1-MMP in cells as as in and cells. The cells were MT1-MMP in both and cells and as the and inactive is of E.I. Ratnikov Monosov G.N. Quigley J.P. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google the individual MT1-MMP has been in cells. the of with the signal αvβ3 integrin not cells mutant MT1-MMP and in cells αvβ3 integrin the the heavy and the Integrin αvβ3 from cells by the and heavy and the The chain is not on these with our expression of MT1-MMP in cells to cell (20Deryugina E.I. Bourdon M.A. Jungwirth K. Smith J.W. Strongin A.Y. Int. J. Cancer. 2000; 86: 15-23Crossref PubMed Scopus (153) Google Scholar, 21Deryugina E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google Scholar). of the wild type MT1-MMP with αvβ3 integrin in cells cell migration on with the essential role of MT1-MMP activity in the of the inactive with αvβ3 integrin in cells did not cell migration of cells and both MT1-MMP To these we cells with to MT1-MMP activity and, the of pro-αv maturation. both on the of αvβ3 integrin in cells and migration of these cells not shown in the cellular MT1-MMP activity and, of the MT1-MMP the in the cells with the This with the of the of pro-αv maturation. of cells with an in the of pro-αv and the heavy α-chain and a in the of the heavy the αv in cells to that in the cells 1 To of and pathways of cell we migration of cells with the the or shown in of cells with the in a their migration to the to and cells. of cells but not cells with a enhanced cell migration of the of the on migration of cells. or to migration of cells these results that αvβ3 integrin by MT1-MMP is likely to be efficient in cell migration to the integrin by the furin-like proprotein migration of cells be associated with outside-in signaling through phosphorylation of the downstream of the integrin-ligand phosphorylation of with the maturation of integrins M. G. Cancer Res. 1999; Google Scholar, S. H. J.S. S.K. K.M. J. Cell Biol. 1995; PubMed Scopus Google Scholar). the processing of the by MT1-MMP affect the of phosphorylation by αvβ3 integrin To that MT1-MMP of cell other αvβ3 integrin of tyrosine phosphorylation of we activation in cells either αvβ3integrin or MT1-MMP with that in the cells co-expressing αvβ3 integrin and MT1-MMP of MT1-MMP of outside-in signaling associated with and the of tyrosine phosphorylation of in cells were as with in and cells and cells were with or and to to 1 cells were and from the cell by with or with our cells of tyrosine phosphorylation of to in or cells with the of tyrosine phosphorylation of in cells. The of in in cells with the This of phosphorylation that cells co-expressing αvβ3 integrin with MT1-MMP be efficient in signal transduction through the pathway. To that of αvβ3 integrin affect outside-in signaling through we tyrosine phosphorylation of in and cells on on at both cell types, in a the of in cells to that in cells. the processing of αvβ3 integrin in these results evidence that MT1-MMP is in the processes the adhesion and migration of breast carcinoma cells on evidence that as MT1-MMP are directly in endoproteolytic of cell surface and αvβ3 integrin (20Deryugina E.I. Bourdon M.A. Jungwirth K. Smith J.W. Strongin A.Y. Int. J. Cancer. 2000; 86: 15-23Crossref PubMed Scopus (153) Google Scholar, 21Deryugina E.I. Ratnikov B. Monosov E. Postnova T.I. DiScipio R. Smith J.W. Strongin A.Y. Exp. Cell Res. 2001; 263: 209-223Crossref PubMed Scopus (333) Google Scholar, Ratnikov E.I. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. T. H. Okada A. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The proteolytic processing of cell surface molecules by MT1-MMP and, other and as and Ratnikov E.I. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google cells to their to the matrix the and a functional between MT1-MMP and αvβ3integrin in tumor cells. the that MT1-MMP exhibits integrin convertase activity and that MT1-MMP is to pro-αv in tumor cells. breast carcinoma MCF7 the MT1-MMP cleavage to at two distinct within a between the and of These a heavy α-chain and a light from the N-terminal of αvβ3integrin E.I. Bourdon M.A. Strongin A. J. Cell Sci. 1997; PubMed Google Scholar, E.I. Bourdon M.A. Strongin A. Res. 1997; Google the is also of processing we that the processing of αv subunit of integrin by MT1-MMP may in cells of processing of pro-αv not affect RGD-ligand binding of αvβ3 cells co-expressing integrin MT1-MMP are efficient to the cells the integrin in outside-in signal transduction through the pathway. Adhesive function of integrins has been associated with the transduction of signals into the of the cell (17Humphries M.J. Curr. Opin. Cell Biol. 1996; 8: 632-640Crossref PubMed Scopus (203) Google Scholar). Integrin ligation normally induces tyrosine phosphorylation through outside-in signaling and activation of cytoplasmic tyrosine kinases and, J.T. Curr. Opin. Cell Biol. 1996; 8: 146-152Crossref PubMed Scopus (277) Google Scholar, F.G. Ruoslahti E. Science. 1999; 285: 1028-1032Crossref PubMed Scopus (3816) Google Scholar). cell types, a known of signaling to be the that in to cell migration F. Exp. Cell Res. 2001; PubMed Scopus Google Scholar). in the of endoproteolytic processing of the signaling function of integrin and cell adhesion (18Berthet V. Rigot V. Champion S. Secchi J. Fouchier F. Marvaldi J. Luis J. J. Biol. Chem. 2000; 275: 33308-33313Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). is in all cell M. G. Cancer Res. 1999; Google that activation of is a efficient cell It has been that the highly conserved of the C-terminal of the domain is in tyrosine phosphorylation of (13Liu S. Calderwood D.A. Ginsberg M.H. J. Cell Sci. 2000; 113: 3563-3571Crossref PubMed Google L. M.A. Ginsberg M.H. S.J. J. Cell Sci. 1995; Google Scholar). of MT1-MMP in the cells in αvβ3 integrin to tyrosine phosphorylation of This our that of αvβ3 integrin and MT1-MMP in cells is a the in our of MT1-MMP and αvβ3 integrin cell adhesion and migration on These are with the that the of the phosphorylation of the intracellular and the binding of cytoskeletal to cytoplasmic of the subunit L. S. F. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). to pro-αv the activation of MT1-MMP in breast carcinoma cells not E.I. Ratnikov Monosov G.N. Quigley J.P. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, I. Weiss S.J. Mol. Biol. Cell. 2000; 11: PubMed Scopus Google Scholar). the enhanced processing of pro-αv by This outside-in signal transduction a and of cells co-expressing αvβ3 integrin and We that MT1-MMP may to pro-αv in processes and by MT1-MMP tumor cells known to activity. has been that in migrating cells MT1-MMP the cell and cell G. J. Curr. Opin. Cell Biol. 1999; 11: PubMed Scopus Google Scholar, K. T. Y. Okada Y. Y. Seiki M. M. Cancer Res. 2000; Google Scholar, H. L. H. Seiki M. Y. Sci. S. A. 1997; PubMed Scopus Google we that MT1-MMP in with the To the of generated from pro-αv the the cellular with the in migrating the cell and the are functional αvβ3 integrin molecules in cells. our and cell migration that MT1-MMP-processed of αvβ3 integrin may be in outside-in signals and, the cell with the This is in the presence of the the maturation of the integrin is is an that the mechanisms MT1-MMP may in a and mature integrins from the cellular pro-αv has the maturation. The of control by MT1-MMP may tumor cells to their to the matrix and, of to the control of integrin