title: Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism.
abstract: 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.
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
authors.forename: Karma
authors.initials: K
authors.lastname: Cinnante
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
authors.forename: William
authors.initials: W
authors.lastname: Scheerer
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
authors.forename: Aubrey C
authors.initials: AC
authors.lastname: Galloway
authors.affiliation: Department of Surgery, New York University School of Medicine, New York, New York 10016 and the Cancer Research Center.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Roses
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California 92037.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Rozanov
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California 92037.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California 92037.
authors.forename: Eok-Soo
authors.initials: ES
authors.lastname: Oh
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California 92037.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California 92037.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pintucci
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016; Department of Cell Biology, New York University School of Medicine, New York, New York 10016. Electronic address: mignap01@med.nyu.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
mesh_terms: D000409:Alanine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D018631:ras Proteins; D000409:Alanine