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.
D'Alessio
Silvia
S
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
Ferrari
Giovanni
G
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
Cinnante
Karma
K
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
Scheerer
William
W
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
Galloway
Aubrey C
AC
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
Roses
Daniel F
DF
Department of Surgery, New York University School of Medicine, New York, New York 10016 and the Cancer Research Center.
Rozanov
Dmitri V
DV
Burnham Institute for Medical Research, La Jolla, California 92037.
Remacle
Albert G
AG
Burnham Institute for Medical Research, La Jolla, California 92037.
Oh
Eok-Soo
ES
Burnham Institute for Medical Research, La Jolla, California 92037.
Shiryaev
Sergey A
SA
Burnham Institute for Medical Research, La Jolla, California 92037.
Strongin
Alex Y
AY
Burnham Institute for Medical Research, La Jolla, California 92037.
Pintucci
Giuseppe
G
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016.
Mignatti
Paolo
P
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.
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
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