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J. Biol. Chem., Vol. 283, Issue 1, 87-99, January 4, 2008

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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, and Paolo Mignatti^||1

From the Departments of Cardiothoracic Surgery, ^||Cell Biology, and Surgery, New York University School of Medicine, New York, New York 10016 and the Cancer Research Center, ^¶Burnham Institute for Medical Research, La Jolla, California 92037

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.

Received for publication, July 5, 2007 , and in revised form, October 9, 2007.

^* This work was supported by U. S. Army Medical Research and Materiel Command Grant DAMD17-17-99-1-9324, National Institutes of Health (NIH) Grants R01 HL070203 and R01 HL070203-03S1, funds from the Dept. of Cardiothoracic Surgery of the New York University School of Medicine, and the Dr. Leo A. Shifrin and Roslyn Myers Breast Cancer Discovery Fund (to P. M.) and by NIH Grants CA83017, CA77470, and RR020843 (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ To whom correspondence should be addressed: New York University Medical Center, 550 First Ave., NBV 15W16, New York, NY 10016. Tel.: 212-263-1478; Fax: 212-263-3101; E-mail: mignap01{at}med.nyu.edu.

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