Src-dependent Phosphorylation of Membrane Type I Matrix Metalloproteinase on Cytoplasmic Tyrosine 573

Membrane type 1 matrix metalloproteinase (MT1-MMP) is a transmembrane MMP that plays important roles in migratory processes underlying tumor invasion and angiogenesis. In addition to its matrix degrading activity, MT1-MMP also contains a short cytoplasmic domain whose involvement in cell locomotion seems important but remains poorly understood. In this study, we show that MT1-MMP is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (Tyr573) and that this phosphorylation requires the kinase Src. Using phosphospecific antibodies recognizing MT1-MMP phosphorylated on Tyr573, we observed that tyrosine phosphorylation of the enzyme is rapidly induced upon stimulation of tumor and endothelial cells with the platelet-derived chemoattractant sphingosine-1-phosphate, suggesting a role in migration triggered by this lysophospholipid. Accordingly, overexpression of a nonphosphorylable MT1-MMP mutant (Y573F) blocked sphingosine-1-phosphate-induced migration of Human umbilical vein endothelial cells and HT-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells). Altogether, these findings strongly suggest that the Src-dependent tyrosine phosphorylation of MT1-MMP plays a key role in cell migration and further emphasize the importance of the cytoplasmic domain of the enzyme in this process. Membrane type 1 matrix metalloproteinase (MT1-MMP) is a transmembrane MMP that plays important roles in migratory processes underlying tumor invasion and angiogenesis. In addition to its matrix degrading activity, MT1-MMP also contains a short cytoplasmic domain whose involvement in cell locomotion seems important but remains poorly understood. In this study, we show that MT1-MMP is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (Tyr573) and that this phosphorylation requires the kinase Src. Using phosphospecific antibodies recognizing MT1-MMP phosphorylated on Tyr573, we observed that tyrosine phosphorylation of the enzyme is rapidly induced upon stimulation of tumor and endothelial cells with the platelet-derived chemoattractant sphingosine-1-phosphate, suggesting a role in migration triggered by this lysophospholipid. Accordingly, overexpression of a nonphosphorylable MT1-MMP mutant (Y573F) blocked sphingosine-1-phosphate-induced migration of Human umbilical vein endothelial cells and HT-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells). Altogether, these findings strongly suggest that the Src-dependent tyrosine phosphorylation of MT1-MMP plays a key role in cell migration and further emphasize the importance of the cytoplasmic domain of the enzyme in this process. The degradation of extracellular matrix (ECM) 3The abbreviations used are: ECM, extracellular matrix; MT1-MMP, membrane-type matrix metalloproteinase; S1P, sphingosine-1-phosphate; siRNA, small interfering RNA; BAEC, bovine aortic endothelial cells; HUVEC, human umbilical vein endothelial cells; HT-1080, human fibrosarcoma cells; FBS, fetal bovine serum; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; MES, 4-morpholineethanesulfonic acid. proteins by members of the matrix metalloproteinases (MMPs) plays a crucial role in several biological processes, including cell attachment, cell migration, invasiveness, cell proliferation, apoptosis, and angiogenesis (1Egeblad M. Werb Z. Nat. Rev. Cancer. 2001; 2: 163-176Crossref Google Scholar, 2Edwards D.R. Murphy G. Nature. 1998; 394: 527-528Crossref PubMed Scopus (136) Google Scholar, 3Folgueras A.R. Pendas A.M. Sanchez L.M. Lopez-Otin C. Int. J. Dev. Biol. 2004; 48: 411-424Crossref PubMed Scopus (491) Google Scholar, 4van Hinsbergh V.W. Engelse M.A. Quax P.H. Arterioscler. Thromb. Vasc. Biol. 2006; 26: 716-728Crossref PubMed Scopus (342) Google Scholar). Among the various MMPs described to date, there is now considerable evidence that MMPs that are intrinsically associated with the plasma membrane because of the presence of a transmembrane domain within their sequence, the so-called membrane type MMPs, represent key components involved in pericellular proteolysis and subsequent cell locomotion and invasion (5Itoh Y. Seiki M. J. Cell. Physiol. 2006; 206: 1-8Crossref PubMed Scopus (424) Google Scholar, 6Haas T.L. Can. J. Physiol. Pharmacol. 2005; 83: 1-7Crossref PubMed Scopus (62) Google Scholar). The prototypical member of this family, MT1-MMP, actively participates in the remodeling of the pericellular ECM by acting as a cellular receptor and activator of proMMP-2 (7Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Crossref PubMed Scopus (2394) Google Scholar) and as a potent matrix-degrading protease that proteolyses a broad spectrum of ECM proteins (8Pei D. Weiss S.J. J. Biol. Chem. 1996; 271: 9135-9140Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar, 9d'Ortho M.P. Will H. Atkinson S. Butler G. Messent A. Gavrilovic J. Smith B. Timpl R. Zardi L. Murphy G. Eur. J. Biochem. 1997; 250: 751-757Crossref PubMed Scopus (392) Google Scholar, 10Hiraoka N. Allen E. Apel I.J. Gyetko M.R. Weiss S.J. Cell. 1998; 95: 365-377Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar) as well as a number of cell surface-associated adhesion receptors (11Kajita M. Itoh Y. Chiba T. Mori H. Okada A. Kinoh H. Seiki M. J. Cell Biol. 2001; 153: 893-904Crossref PubMed Scopus (633) Google Scholar, 12Belkin A.M. Akimovm S.S. Zaritskaya L.S. Ratnikov B.I. Deryugina E.I. Strongin A.Y. J. Biol. Chem. 2001; 276: 18415-18422Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar). These events are likely to be important in vivo because MT1-MMP null mice fail to thrive and have a markedly reduced lifespan (13Holmbeck K. Bianco P. Caterina J. Yamada S. Kromer M. Kuznetsov S.A. Mankani M. Robey P.G. Poole A.R. Pidoux I. Ward J.M. Birkedal-Hansen H. Cell. 1999; 99: 81-92Abstract Full Text Full Text PDF PubMed Scopus (1115) Google Scholar, 14Zhou Z. Apte S.S. Soininen R. Cao R. Baaklini G.Y. Rauser R.W. Wang J. Cao Y. Tryggvason K. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4052-4057Crossref PubMed Scopus (697) Google Scholar). In addition to its role in normal physiology, MT1-MMP is also overexpressed in many types of tumors (15Nakada M. Nakamura H. Ikeda E. Fujimoto N. Yamashita J. Sato H. Seiki M. Okada Y. Am. J. Pathol. 1999; 154: 417-428Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 16Zhai Y. Hotary K.B. Nan B. Bosch F.X. Munoz N. Weiss S.J. Cho K.R. Cancer Res. 2005; 65: 6543-6550Crossref PubMed Scopus (100) Google Scholar), and this overexpression appears crucial for tumor cell migration and invasion. For example, MT1-MMP-mediated degradation of some ECM proteins, such as the laminin-5γ2 chain (17Koshikawa N. Minegishim T. Sharabi A. Quaranta V. Seiki M. J. Biol. Chem. 2005; 280: 88-93Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), stimulates migration, whereas proteolysis of the dense, cross-linked meshwork of type I collagen fibrils by the enzyme confers neoplastic cells with tissue-invasive activity (18Sabeh F. Ota I. Holmbeck K. Birkedal-Hansen H. Soloway P. Balbin M. Lopez-Otin C. Shapiro S. Inada M. Krane S. Allen E. Chung D. Weiss S.J. J. Cell Biol. 2004; 167: 769-781Crossref PubMed Scopus (493) Google Scholar) and sustains tumor cell growth in otherwise growth-restrictive three-dimensional matrices (19Hotary K.B. Allen E.D. Brooks P.C. Datta N.S. Long M.W. Weiss S.J. Cell. 2003; 114: 33-45Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar). Despite its importance to normal physiology and in the development of malignancy, the mechanisms underlying MT1-MMP-mediated cell invasion remain incompletely understood. During cell migration, MT1-MMP localizes predominantly to the cell adherent edge at the migration front, an appropriate location for the degradation of the ECM barrier (20Sato T. del Carmen Ovejero M. Hou P. Heegaard A.M. Kumegawa M. Foged N.T. Delaisse J.M. J. Cell Sci. 1997; 110: 589-596Crossref PubMed Google Scholar). In addition, we and others have shown that MT1-MMP is preferentially localized into caveolae, specialized domains of the plasma membrane (21Annabi B. Lachambre M-P. Bousquet-Gagnon N. Pagé M. Gingras D. R. Biochem. J. 2001; PubMed Scopus (136) Google Scholar, A. R. M. B. S. Cell Res. 2001; PubMed Scopus Google Scholar), and this to the of its activity by and of the enzyme S. M. M. F. Biol. Cell. 2004; PubMed Scopus Google Scholar, A. Murphy G. C. J. Cell Sci. 2003; PubMed Scopus Google Scholar). In addition to the importance of MT1-MMP-mediated of ECM proteins for the of cell migration, that the cytoplasmic domain of the enzyme also a role in this process. For example, MT1-MMP lacking the cytoplasmic domain remain localized at the cell and failed to migration, suggesting an important role for the enzyme cytoplasmic sequence in the of its activity K. H. S. J. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. K. Wang Weiss S.J. J. D. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, T. Itoh Y. I. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google Scholar). In this the cytoplasmic domain of MT1-MMP shown to be involved in several of enzyme activity, including the of K. J. D. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Deryugina E.I. Ratnikov B.I. Strongin A.Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), the of the enzyme to H. L. Sato H. Seiki M. Y. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus (367) Google Scholar), the of the extracellular kinase D. Bousquet-Gagnon N. S. Lachambre M-P. B. R. 2001; PubMed Scopus Google Scholar), and its with a number of proteins such as T. I. T. Itoh Y. Sato H. T. Okada Y. Seiki M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), the of T. Itoh Y. I. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google Scholar), and L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google Scholar). the mechanisms by the MT1-MMP cytoplasmic sequence is in these processes remain poorly that an important of this domain in the of the enzyme with chemoattractant such as a by S. Gingras D. R. 2004; PubMed Scopus Google Scholar). In this study, we that MT1-MMP is within its cytoplasmic in a Src-dependent tyrosine phosphorylation is upon stimulation of endothelial and tumor cells with and seems important for tumor and endothelial cell migration triggered by this and and and growth and and The and and and and and antibodies and antibodies and and for and and Cell aortic endothelial cells human umbilical vein endothelial cells human fibrosarcoma cells and cells and at in a in with with bovine growth and in endothelial cell growth with fetal bovine human growth endothelial growth human growth growth and HT-1080 in with 1 FBS, and in with with FBS, and the human MT1-MMP, its cytoplasmic and have described D. Bousquet-Gagnon N. S. Lachambre M-P. B. R. 2001; PubMed Scopus Google Scholar, S. Gingras D. R. 2004; PubMed Scopus Google Scholar). The MT1-MMP cytoplasmic and by as described L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google Scholar). The MT1-MMP in the in the of the enzyme and the The and by of cells the HT-1080 cells the and with of the to the of phosphospecific antibodies by and on the human MT1-MMP cytoplasmic sequence and by The by The with the with a and and to the by a the of the antibodies the phosphorylated antibodies for at with a of the the and as described the to in CHAPS, proteins with a Hinsbergh V.W. Engelse M.A. Quax P.H. Arterioscler. Thromb. Vasc. Biol. 2006; 26: 716-728Crossref PubMed Scopus (342) Google Scholar, Y. Seiki M. J. Cell. Physiol. 2006; 206: 1-8Crossref PubMed Scopus (424) Google Scholar, 6Haas T.L. Can. J. Physiol. Pharmacol. 2005; 83: 1-7Crossref PubMed Scopus (62) Google Scholar, H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Crossref PubMed Scopus (2394) Google Scholar) at for and at for for and for For the for at in and for in and on and as described a as described L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google Scholar). cells in into of and a of at by of at of of the to by the addition of of in MES, and with of and in The at for a For of the the to the of the in and at for 1 of and with and cells to for in The cells at with 1 an of by for with 1 The cells in 1 by for at and a by the and have described L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google Scholar). of proteins in 1 1 1 at in the presence of of and the by the with in for and by The proteins blocked at with with bovine and for 1 at with the 1 of with and the by the and cells on with and with 1 for of with for the cells with for with for blocked bovine in for and with antibodies and MT1-MMP The cells with The with and a Cell of BAEC, HUVEC, cells with of MT1-MMP, on with The in and the with with 1 cells in of cell at a of and into the of The at in for and cells that The are as the of S. Gingras D. R. 2004; PubMed Scopus Google Scholar). by of by the For the of the and as described S. Gingras D. R. 2004; PubMed Scopus Google Scholar), and MT1-MMP by For HT-1080 by of of proMMP-2 in as described (21Annabi B. Lachambre M-P. Bousquet-Gagnon N. Pagé M. Gingras D. R. Biochem. J. 2001; PubMed Scopus (136) Google Scholar). 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Google Scholar), is that the have induced a in the enzyme MT1-MMP tyrosine of the cytoplasmic domain tyrosine phosphorylation the MT1-MMP cytoplasmic sequence contains tyrosine residue at of the we the of of MT1-MMP lacking this overexpression of the and tyrosine further suggesting that the tyrosine residue of MT1-MMP is the of phosphorylation that MT1-MMP is phosphorylated on tyrosine we cells of MT1-MMP with shown in of MT1-MMP cells in the of at well observed that the at a to MT1-MMP whereas the with associated with of the These likely to represent MT1-MMP because overexpression of the mutant the tyrosine phosphorylation of MT1-MMP these also by phosphospecific MT1-MMP antibodies these that MT1-MMP is in cells and that this its unique cytoplasmic tyrosine and for MT1-MMP on that with MT1-MMP, we the tyrosine phosphorylation of MT1-MMP is involved in its with L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. 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J. 2001; PubMed Scopus (136) Google Scholar) endothelial A. R. M. B. S. Cell Res. 2001; PubMed Scopus Google Scholar) we observed that the of the of the enzyme associated with these domains by overexpression of by of the phosphorylation within the cytoplasmic domain The of MT1-MMP associated with for the in the presence of seems in caveolae, whereas the the mutant associated with by the presence of Src. these that is involved in the tyrosine phosphorylation of MT1-MMP, the phosphorylation of the enzyme its of antibodies represent an to the role of phosphorylation in events Am. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). antibodies recognizing the phosphorylated of MT1-MMP, with a the phosphorylated sequence of the and the antibodies by a by the of the phosphorylated MT1-MMP, antibodies with the the and their to phosphorylated MT1-MMP the the of the phosphorylated of MT1-MMP, whereas of the antibodies with the the antibodies MT1-MMP in cells MT1-MMP and in with with the the antibodies the MT1-MMP (Y573F) in the presence of further their MT1-MMP that is on its cytoplasmic tyrosine residue The of MT1-MMP phosphorylation by the phosphospecific antibodies also to that observed the that these antibodies phosphorylated MT1-MMP antibodies MT1-MMP and show a in further that antibodies are to the of and Cell MT1-MMP is a platelet-derived that as a chemoattractant for endothelial and tumor cells PubMed Scopus Google Scholar). shown that MT1-MMP with to endothelial cell migration and their into S. Gingras D. R. 2004; PubMed Scopus Google Scholar). MT1-MMP is in to human fibrosarcoma and human umbilical endothelial vein cells for various of with S1P, and the of MT1-MMP phosphorylation by that the phosphospecific antibodies in and that antibodies failed to the enzyme cells L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google Scholar), and the presence of phosphorylated MT1-MMP in the the shown in stimulation of cells with in a of MT1-MMP, with a phosphorylation at phosphorylation predominantly observed for the of the but a of MT1-MMP also strongly phosphorylated of stimulation with The of phosphorylation of this rapidly the of MT1-MMP in these cells K. J. H. J. Biochem. J. 1998; PubMed Scopus Google Scholar). The addition of a kinase markedly phosphorylation of MT1-MMP, suggesting the importance of in this process. In a MT1-MMP phosphorylation in HUVEC, with a at and this phosphorylation to the involvement of kinase of MT1-MMP is localized to and with phosphorylated and L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google and B. Lachambre M-P. Bousquet-Gagnon N. Pagé M. Gingras D. R. Biochem. J. 2001; PubMed Scopus (136) Google Scholar) and overexpression of appears to the of MT1-MMP in caveolae, we the of phosphorylation of MT1-MMP on its in endothelial cells In a and of observed in with the by stimulation of the cells with induced a of the enzyme to the cell and this with a of with within these and The of at the cell in cells that tyrosine phosphorylation of the enzyme an important role in cell migration induced by MT1-MMP for and Cell is well that MT1-MMP plays a key role in cell migration in Y. Seiki M. J. Cell. Physiol. 2006; 206: 1-8Crossref PubMed Scopus (424) Google Scholar). the role of phosphorylated MT1-MMP in tumor and endothelial cell migration, fibrosarcoma endothelial and cells with of In cells that of MT1-MMP and overexpression of MT1-MMP a on migration, but the mutant strongly migration induced by suggesting that the mutant in a and S. Gingras D. R. 2004; PubMed Scopus Google Scholar), overexpression of MT1-MMP in BAEC, are of the induced a in migration induced by this markedly reduced upon of the nonphosphorylable MT1-MMP These that the tyrosine residue located within the MT1-MMP cytoplasmic domain plays an important role in cell migration, by acting as a tyrosine phosphorylation within the the involvement of MT1-MMP in cell migration in of its activity a of ECM N. Allen E. Apel I.J. Gyetko M.R. Weiss S.J. Cell. 1998; 95: 365-377Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar, N. Minegishim T. Sharabi A. Quaranta V. Seiki M. J. Biol. Chem. 2005; 280: 88-93Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, F. Ota I. Holmbeck K. Birkedal-Hansen H. Soloway P. Balbin M. Lopez-Otin C. Shapiro S. Inada M. Krane S. Allen E. Chung D. Weiss S.J. J. Cell Biol. 2004; 167: 769-781Crossref PubMed Scopus (493) Google Scholar, K.B. Allen E.D. Brooks P.C. Datta N.S. Long M.W. Weiss S.J. Cell. 2003; 114: 33-45Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar) cell surface-associated (11Kajita M. Itoh Y. Chiba T. Mori H. Okada A. Kinoh H. Seiki M. J. Cell Biol. 2001; 153: 893-904Crossref PubMed Scopus (633) Google Scholar, 12Belkin A.M. Akimovm S.S. Zaritskaya L.S. Ratnikov B.I. Deryugina E.I. Strongin A.Y. J. Biol. Chem. 2001; 276: 18415-18422Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar) proteins, there is also evidence an important role of the short cytoplasmic domain of the enzyme in this For example, the migration of a number of tumor K. H. S. J. J. J. Biol. 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The in the suggest that the importance of the cytoplasmic domain in cell migration also be to the phosphorylation of the unique tyrosine residue located within this we observed that proteins associated with the MT1-MMP and to the strongly suggesting that represent phosphorylated of by the of phosphorylation by of this tyrosine residue as well as by the of the phosphorylated of the enzyme by phosphospecific antibodies the phosphorylated these antibodies MT1-MMP lacking a tyrosine residue located within its these at the used in study, MT1-MMP phosphorylated on its unique cytoplasmic tyrosine The tyrosine phosphorylation of MT1-MMP of and by overexpression of a that a kinase by plays an role in this these also induced phosphorylation of to the of MT1-MMP with and L. C. S. Y. C. Murphy G. Gingras D. R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (136) Google Scholar), that this for a of the phosphorylation of we observed that of the and the of phosphorylation of MT1-MMP, suggesting that the of the tyrosine phosphorylation of MT1-MMP to cells but also be in cells with the chemoattractant tyrosine phosphorylation of MT1-MMP with the of the enzyme at the cell stimulation with S1P, the that this phosphorylation in the migratory processes induced by this phosphorylation of MT1-MMP induced a of the enzyme with a that shown to be important for endothelial cell A. K. H. V. S. J. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). The importance of MT1-MMP phosphorylation is also by the of a nonphosphorylable MT1-MMP mutant to migration of cells MT1-MMP, such as and HUVEC, as well as by its to stimulate migration in BAEC, a cell that of the tyrosine phosphorylation of MT1-MMP the of the enzyme with this for the of migration and of endothelial cells S. 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In this the that tyrosine phosphorylation of the MT1-MMP cytoplasmic domain plays an important role in tumor and endothelial cell migration that interfering with the involved in this represent an to tumor triggered by this crucial for on and for of

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