Tissue Inhibitor of Metalloproteinases-2 Binding to Membrane-type 1 Matrix Metalloproteinase Induces MAPK Activation and Cell Growth by a Non-proteolytic Mechanism

Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with a short cytoplasmic domain and an extracellular catalytic domain, controls a variety of physiological and pathological processes through the proteolytic degradation of extracellular or transmembrane proteins. MT1-MMP forms a complex on the cell membrane with its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2). Here we show that, in addition to extracellular proteolysis, MT1-MMP and TIMP-2 control cell proliferation and migration through a non-proteolytic mechanism. TIMP-2 binding to MT1-MMP induces activation of ERK1/2 by a mechanism that does not require the proteolytic activity and is mediated by the cytoplasmic tail of MT1-MMP. MT1-MMP-mediated activation of ERK1/2 up-regulates cell migration and proliferation in vitro independently of extracellular matrix proteolysis. Proteolytically inactive MT1-MMP promotes tumor growth in vivo, whereas proteolytically active MT1-MMP devoid of cytoplasmic tail does not have this effect. These findings illustrate a novel role for MT1-MMP-TIMP-2 interaction, which controls cell functions by a mechanism independent of extracellular matrix degradation. Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with a short cytoplasmic domain and an extracellular catalytic domain, controls a variety of physiological and pathological processes through the proteolytic degradation of extracellular or transmembrane proteins. MT1-MMP forms a complex on the cell membrane with its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2). Here we show that, in addition to extracellular proteolysis, MT1-MMP and TIMP-2 control cell proliferation and migration through a non-proteolytic mechanism. TIMP-2 binding to MT1-MMP induces activation of ERK1/2 by a mechanism that does not require the proteolytic activity and is mediated by the cytoplasmic tail of MT1-MMP. MT1-MMP-mediated activation of ERK1/2 up-regulates cell migration and proliferation in vitro independently of extracellular matrix proteolysis. Proteolytically inactive MT1-MMP promotes tumor growth in vivo, whereas proteolytically active MT1-MMP devoid of cytoplasmic tail does not have this effect. These findings illustrate a novel role for MT1-MMP-TIMP-2 interaction, which controls cell functions by a mechanism independent of extracellular matrix degradation. Membrane-type 1 matrix metalloproteinase (MT1-MMP), 2The abbreviations used are:MT1-MMPmembrane-type 1 matrix metalloproteinaseMAPKmitogen-activated protein kinaseERK1/2extracellular signal-regulated kinases 1 and 2MEK1/2MAPK kinases 1 and 2MMP-2matrix metalloproteinase-2TIMP-1tissue inhibitor of metalloproteinases-1TIMP-2tissue inhibitor of metalloproteinases-2FCSfetal calf serumCATcatalytic domainPEXhemopexin domainPBSphosphate-buffered salineCTcytoplasmic tailBSAbovine serum albuminFGF-2fibroblast growth factor-2wtwild typeECMextracellular matrixDOXdoxycycline the prototype member of the MT-MMP subclass of matrix metalloproteinases (MMP), is a cell membrane-bound proteinase with an extracellular catalytic site and a 20-amino acid cytoplasmic tail (1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Crossref PubMed Scopus (2379) Google Scholar). MT1-MMP degrades a variety of extracellular matrix components, including fibrillar collagen, and activates the proenzyme form of MMP-2 (gelatinase A) (2Mignatti P. Rifkin D.B. Adv. Cancer Res. 2000; 78: 103-157Crossref PubMed Google Scholar). The analysis of the phenotype of mice genetically deficient in MT1-MMP has shown important roles of this enzyme in development, connective tissue metabolism, and angiogenesis (3Holmbeck K. Bianco P. Caterina J. Yamada S. Kromer M. Kuznetsov S.A. Mankani M. Gehron Robey P. Robin Poole A. Pidoux I. Ward J.M. Birkedal-Hansen H. Cell. 1999; 99: 81-92Abstract Full Text Full Text PDF PubMed Scopus (1112) Google Scholar, 4Zhou 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 (690) Google Scholar, 5Oblander S.A. Zhou Z. Galvez B.G. Starcher B. Shannon J.M. Durbeej M. Arroyo A.G. Tryggvason K. Apte S.S. Dev. Biol. 2005; 277: 255-269Crossref PubMed Scopus (112) Google Scholar). In addition, the expression of high levels of MT1-MMP in invasive tumors has implicated MT1-MMP as an important component of the proteolytic mechanisms of cancer invasion and metastasis (2Mignatti P. Rifkin D.B. Adv. Cancer Res. 2000; 78: 103-157Crossref PubMed Google Scholar, 6Deryugina E.I. Quigley J.P. Cancer Metastasis Rev. 2006; 25: 9-34Crossref PubMed Scopus (1651) Google Scholar, 7Hotary 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 Google Scholar, I. K. Birkedal-Hansen H. P. M. S. M. S. Allen E. Weiss S.J. J. Biol. PubMed Scopus Google Scholar). 1 matrix metalloproteinase protein extracellular signal-regulated kinases 1 and kinases 1 and matrix tissue inhibitor of tissue inhibitor of metalloproteinases-2 calf serum catalytic domain domain cytoplasmic tail serum growth extracellular matrix MT1-MMP forms a complex with MMP-2 and its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2). In this the domain of TIMP-2 to the catalytic site of whereas the domain of TIMP-2 the domain of MMP-2 I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). TIMP-2 is a member of a of through that to active in a and activity R. H. Res. 2003; PubMed Scopus Google Scholar). In addition, and TIMP-2 control cell and through mechanisms T. K. E. Shinagawa A. J. Sci. 1994; PubMed Google Scholar, T. K. K. E. K. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). TIMP-2 cell and proliferation J. Biol. Full Text Full Text PDF PubMed Scopus Google and cell proliferation in as as tumor growth and angiogenesis in by an mechanism S. Cancer Res. PubMed Scopus Google Scholar, H. T. R. Cell. 2003; 114: Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. T. B. J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of TIMP-2 mediated by the cell membrane that the activity of TIMP-2 The MT1-MMP to as a cell membrane binding site for a protein with growth and the in MT1-MMP of a cytoplasmic domain to the that MT1-MMP binding of Here we show that TIMP-2 binding to MT1-MMP activates the extracellular signal-regulated which up-regulates cell proliferation and migration by a mechanism independent of the proteolytic activity of MT1-MMP. TIMP-2 a R. or the catalytic domain of TIMP-2 the TIMP-2 and with the and to the of MT1-MMP to and or and to the catalytic domain of MT1-MMP in and by protein and mice genetically deficient in or in with calf serum and of and with a for the and with MT1-MMP in the and with the in and in of in the or of 1 and for MT1-MMP expression by and of and of with the MT1-MMP expression levels and used for the TIMP-2 and MT1-MMP MT1-MMP of the catalytic and with and the and E. The with 1 for by and on in 1 1 and the the of with 1 and and in and The by a in with 1 1 and The protein a and on a with 1 The protein with an in 1 with a and The MT1-MMP tail of the of the domain and the of MT1-MMP to the of the cytoplasmic tail The in as J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. Biol. Full Text Full Text PDF PubMed Scopus Google and the protein by The catalytic domain of MT1-MMP in E. and to the catalytic activity as B. E. J. A. 2000; PubMed Scopus Google Scholar). The for the MT1-MMP with of the J. M. S. J. Biol. Full Text Full Text PDF PubMed Scopus Google a S. and J. Cao of of The for the MT1-MMP with of the cytoplasmic tail and K. H. S. J. J. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google a J. of The a of the cytoplasmic and transmembrane the and and the have J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, B. B. E.I. PubMed Scopus Google Scholar). in P. and to by and MT1-MMP in in 1 of the and of the with for and used for the as R. A. P. J. 2003; PubMed Scopus Google Scholar). cell as R. A. P. J. 2003; PubMed Scopus Google with activation by the TIMP-2 and binding to the of a with or or or with as a control of protein in of for The with in for TIMP-2 or in of for of as a control of TIMP-2 or with to TIMP-2 in of for The by with and with in of for 1 with and with to the The by of 1 and with a in TIMP-2 and binding to the MT1-MMP catalytic domain the of a for with TIMP-2 or or with as a control in of with in for in of the for of as a control of The with and the catalytic domain of MT1-MMP in for The by with in and for 1 with and with to the The by 1 and with a in in in the or of 1 in the of with of TIMP-2 or and the inhibitor or as a control to the the on the of the membrane with and a The as the of the migration of or in and with with the of a in to the for with control or TIMP-2 as or with and the of in a an P. J. PubMed Scopus Google Scholar). in in the or of 1 in the TIMP-2 or the inhibitor to the and the and by the the in and proliferation to the of in by to the in with the MT1-MMP or E.I. Quigley J.P. J. Biol. Full Text Full Text PDF PubMed Scopus Google in of cell in the of mice to growth by of and of the by the with or the and as R. S. J. 2006; PubMed Scopus Google Scholar, J. M. 2005; PubMed Scopus Google Scholar). in the of used as in analysis of by with and of The as the the of the and that of the analysis by the with and and MT1-MMP and TIMP-2 ERK1/2 with a the that TIMP-2 binding to MT1-MMP we used with MT1-MMP control by the or levels of and TIMP-2 E.I. Quigley J.P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). or of the of or in of MT1-MMP expression and The MT1-MMP by the active and by TIMP-2 or by the inhibitor E.I. Quigley J.P. J. Biol. Full Text Full Text PDF PubMed Scopus Google TIMP-2 to the of in the or of and the for ERK1/2 activation of and with S. B. R. 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Full Text Full Text PDF PubMed Scopus Google Scholar). not ERK1/2 in and the of the in the MT1-MMP to that of its MT1-MMP that TIMP-2 binding to MT1-MMP up-regulates ERK1/2 TIMP-2 of ERK1/2 the and in the or of TIMP-2 activation of ERK1/2 of MT1-MMP we the on ERK1/2 activation of a TIMP-2 devoid of activity J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The and that ERK1/2 activation as as TIMP-2 in on that not MT1-MMP. does not to the catalytic domain of we of with of MT1-MMP. this we used the binding The that and to an MT1-MMP with acid in the catalytic domain that the proteolytic activity E.I. Quigley J.P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). 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Here we that MT1-MMP binding of TIMP-2 activates by a non-proteolytic mechanism that controls cell proliferation and These on the MT1-MMP expression and addition of TIMP-2 to the ERK1/2 activation and the of TIMP-2 with a effect. addition of TIMP-2 to devoid of MT1-MMP or that MT1-MMP devoid of does not have TIMP-2 with and MT1-MMP levels with the of that MT1-MMP is the or the TIMP-2 binding site in the we is with binding and that the on cell of high binding site as MT1-MMP I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. Cao J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). findings show that the mechanism by TIMP-2 binding to MT1-MMP is independent of the proteolytic activity of ERK1/2 activation is by inactive MT1-MMP and by TIMP-2 devoid of the MT1-MMP catalytic domain ERK1/2 activation as with MT1-MMP for TIMP-2 and TIMP-2 that MT1-MMP activation of MMP-2 ERK1/2 in of MT1-MMP activity by does not have this effect. the of TIMP-2 is not mediated by its to MMP-2 in with MT1-MMP I. J. Biol. Full Text Full Text PDF PubMed Scopus Google or by of MT1-MMP. that activates ERK1/2 addition to does not to the catalytic site J. Biol. Full Text Full Text PDF PubMed Scopus Google that the of TIMP-2 TIMP-2 with of MT1-MMP or in addition to the active site binding with MT1-MMP that TIMP-2 and to the domain the of MT1-MMP. These with a that the MT1-MMP domain does not TIMP-2 E. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). this including the of and for the binding that the of TIMP-2 mediated by its with the domain the of MT1-MMP. that ERK1/2 activation by TIMP-2 binding to MT1-MMP the cytoplasmic tail not the catalytic activity of MT1-MMP. have shown that MT1-MMP expression up-regulates activation of ERK1/2 or kinases by or mechanisms that require the catalytic activity and cytoplasmic tail of MT1-MMP S. B. R. PubMed Scopus Google Scholar, M. E. Galvez B.G. J.M. A. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In proteolytically inactive MT1-MMP activation J. P. M. S. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). to of the is in the inactive MT1-MMP The of MT1-MMP in on the of by and expression of the levels of MT1-MMP to ERK1/2 In addition, not the and of TIMP-2 on activation of has shown that MT1-MMP devoid of cytoplasmic tail ERK1/2 activation and cell proliferation by a mechanism on growth and by including TIMP-2 K. Allen E. Birkedal-Hansen H. K. Y. Weiss S.J. Dev. 2005; PubMed Scopus Google Scholar). The we used not growth H. J. PubMed Scopus Google Scholar). not the that the of activation of ERK1/2 in cell is mediated by MT1-MMP with or growth growth have shown that cell migration and invasion in vitro and in require the proteolytic activity not the cytoplasmic tail of MT1-MMP and that TIMP-2 tumor cell growth and invasion in vitro and in 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 Google Scholar, I. K. Birkedal-Hansen H. P. M. S. M. S. Allen E. Weiss S.J. J. Biol. PubMed Scopus Google Scholar, K. Allen E. Birkedal-Hansen H. K. Y. Weiss S.J. Dev. 2005; PubMed Scopus Google Scholar, I. H. K. Birkedal-Hansen H. Allen E.D. Weiss S.J. J. Biol. PubMed Scopus Google Scholar, S. K.B. I. Birkedal-Hansen H. K. Allen E.D. Weiss S.J. J. 2005; PubMed Scopus Google Scholar). These with TIMP-2 to to 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 Google Scholar, I. K. Birkedal-Hansen H. P. M. S. M. S. Allen E. Weiss S.J. J. Biol. PubMed Scopus Google Scholar, I. H. K. Birkedal-Hansen H. Allen E.D. Weiss S.J. J. Biol. PubMed Scopus Google Scholar, S. K.B. I. Birkedal-Hansen H. K. Allen E.D. Weiss S.J. J. 2005; PubMed Scopus Google Scholar, A. A. J. Natl. Cancer PubMed Scopus Google Scholar). These TIMP-2 to in or Z. H. K. Google Scholar, J.P. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Y. H. 1999; PubMed Scopus Google Scholar, M. 114: PubMed Scopus Google and to the of TIMP-2 for MT1-MMP I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. Cao J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In we that ERK1/2 activation is by TIMP-2 to to the mechanism we is mediated by TIMP-2 to in or have the of the proteolytic activity of MT1-MMP in the extracellular matrix degradation for cell migration and show that MT1-MMP to cell migration and proliferation in vitro the of through a mechanism that the cytoplasmic tail of MT1-MMP. mechanism does not the for proteolytic degradation of the which cell invasion of complex extracellular and promotes cell proliferation through a variety of the by MT1-MMP through its cytoplasmic tail the with and The is a complex degradation a of (2Mignatti P. Rifkin D.B. Adv. Cancer Res. 2000; 78: 103-157Crossref PubMed Google Scholar, P. Rifkin D.B. Rev. PubMed Scopus Google Scholar). MT1-MMP is for the degradation of important components, to degradation. MT1-MMP by TIMP-2 and the cell with and as the levels of as as MT1-MMP have with an phenotype in a variety of tumors Y. PubMed Scopus Google Scholar). ERK1/2 activation TIMP-2 binding to MT1-MMP the of the cytoplasmic have shown that is by a mechanism of tumor or with a of cell migration M. E. R. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). to that is in the or of we that the of or of on ERK1/2 activation is not by of this site in the cytoplasmic tail with proteins. and acid and the of the cytoplasmic variety of tumors high levels of MT1-MMP and of which have with an phenotype Y. PubMed Scopus Google Scholar, Y. K.B. B. Weiss S.J. Cancer Res. 2005; PubMed Scopus Google Scholar, Y. H. Takino T. Y. Okada Y. Shinagawa A. H. Seiki M. Cancer Res. Google Scholar, H. H. M. K. M. H. Seiki M. Okada Y. Cancer Res. Google Scholar). in show that MT1-MMP to tumor cell proliferation by a cytoplasmic mechanism to degradation. proteolytically inactive MT1-MMP to a that of tumors MT1-MMP. the proliferation and and the of the tumor on 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 Google Scholar, I. K. Birkedal-Hansen H. P. M. S. M. S. Allen E. Weiss S.J. J. Biol. PubMed Scopus Google Scholar, K. Allen E. Birkedal-Hansen H. K. Y. Weiss S.J. Dev. 2005; PubMed Scopus Google Scholar, I. H. K. Birkedal-Hansen H. Allen E.D. Weiss S.J. J. Biol. PubMed Scopus Google Scholar, S. K.B. I. Birkedal-Hansen H. K. Allen E.D. Weiss S.J. J. 2005; PubMed Scopus Google we that the of tumors proteolytically inactive MT1-MMP the of proteolytic activity and degradation. MT1-MMP proteolytic activity does not H. S.J. B. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). is a inactive in for a role of TIMP-2 in the growth of TIMP-2 is in MT1-MMP or MT1-MMP devoid of cytoplasmic tail that TIMP-2 on tumor growth in the of MT1-MMP. to the role of in tumor growth in analysis is by of MT1-MMP with a variety of extracellular including and which to through MT1-MMP. the that MT1-MMP to tumor growth in with a mechanism mediated by its cytoplasmic The non-proteolytic of on have roles in in physiological and pathological The TIMP-2 that ERK1/2 in the of the for TIMP-2 binding to MT1-MMP I. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. Cao J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of MT1-MMP of with in and development, and by of (3Holmbeck K. Bianco P. Caterina J. Yamada S. Kromer M. Kuznetsov S.A. Mankani M. Gehron Robey P. Robin Poole A. Pidoux I. Ward J.M. Birkedal-Hansen H. Cell. 1999; 99: 81-92Abstract Full Text Full Text PDF PubMed Scopus (1112) Google Scholar, 4Zhou 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 (690) Google Scholar, 5Oblander S.A. Zhou Z. Galvez B.G. Starcher B. Shannon J.M. Durbeej M. Arroyo A.G. Tryggvason K. Apte S.S. Dev. Biol. 2005; 277: 255-269Crossref PubMed Scopus (112) Google Scholar, K. Bianco P. K. Yamada S. Birkedal-Hansen H. J. Biol. 2003; PubMed Scopus Google Scholar). has that this phenotype the of MT1-MMP proteolytic on of the non-proteolytic role of MT1-MMP in ERK1/2 is to that the phenotype of and in is by the that in the MT1-MMP is and with the the site of growth S.S. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). mice not the phenotype of MT1-MMP mice Z. R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). and which to MT1-MMP with high H. P. A. H. M. R. J. Biol. Full Text Full Text PDF PubMed Scopus Google in TIMP-2 In the show a mechanism through which MT1-MMP and TIMP-2 of this mechanism have important for of physiological and pathological and for the of to control to and for the of the MT1-MMP Apte for the and and for the of with

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