Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism

Silvia D'Alessio, Giovanni Ferrari, Karma Cinnante, William Scheerer, Aubrey C. Galloway, Daniel F. Roses, Dmitri V. Rozanov, Albert G. Remacle, Eok Soo Oh, Sergey A. Shiryaev, Alex Y. Strongin, Giuseppe Pintucci, Paolo Mignatti

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78 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)87-99
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number1
DOIs
StatePublished - Jan 4 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    D'Alessio, S., Ferrari, G., Cinnante, K., Scheerer, W., Galloway, A. C., Roses, D. F., Rozanov, D. V., Remacle, A. G., Oh, E. S., Shiryaev, S. A., Strongin, A. Y., Pintucci, G., & Mignatti, P. (2008). Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism. Journal of Biological Chemistry, 283(1), 87-99. https://doi.org/10.1074/jbc.M705492200