TIMP-2 Interaction with MT1-MMP Activates the AKT Pathway and Protects Tumor Cells from Apoptosis.
Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, degrades a variety of extracellular matrix (ECM) components. In addition, MT1-MMP activates intracellular signaling through proteolysis-dependent and independent mechanisms. We have previously shown that binding of tissue inhibitor of metalloproteinases-2 (TIMP-2) to MT1-MMP controls cell proliferation and migration, as well as tumor growth in vivo by activating the Ras-extracellular signal regulated kinase-1 and -2 (ERK1/2) pathway through a mechanism that requires the cytoplasmic but not the proteolytic domain of MT1-MMP. Here we show that in MT1-MMP expressing cells TIMP-2 also induces rapid and sustained activation of AKT in a dose- and time-dependent manner and by a mechanism independent of the proteolytic activity of MT1-MMP. Fibroblast growth factor receptor-1 mediates TIMP-2 induction of ERK1/2 but not of AKT activation; however, Ras activation is necessary to transduce the TIMP-2-activated signal to both the ERK1/2 and AKT pathways. ERK1/2 and AKT activation by TIMP-2 binding to MT1-MMP protects tumor cells from apoptosis induced by serum starvation. Conversely, TIMP-2 upregulates apoptosis induced by three-dimensional type I collagen in epithelial cancer cells. Thus, TIMP-2 interaction with MT1-MMP provides tumor cells with either pro- or anti-apoptotic signaling depending on the extracellular environment and apoptotic stimulus.
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York, United States of America.
Cristina
C
Valacca
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York, United States of America.
Evelyne
E
Tassone
Department of Medicine, New York University School of Medicine, New York, New York, United States of America; Department of Cell Biology, New York University School of Medicine, New York University School of Medicine, New York, New York, United States of America.
Paolo
P
Mignatti
D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D060066:Protein Interaction Maps; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D017468:Receptors, Fibroblast Growth Factor; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14