Selective involvement of TIMP-2 in the second activational cleavage of pro-MMP-2: refinement of the pro-MMP-2 activation mechanism.
A tissue inhibitor of metalloproteinases-2 (TIMP-2)-independent mechanism for generating the first activational cleavage of pro-matrix metalloproteinase-2 (MMP-2) was identified in membrane type-1 MMP (MT1-MMP)-transfected MCF-7 cells and confirmed in TIMP-2-deficient fibroblasts. In contrast, the second MMP-2-activational step was found to be TIMP-2 dependent in both systems. MMP-2 hemopexin C-terminal domain was found to be critical for the first step processing, confirming a need for membrane tethering. We propose that the intermediate species of MMP-2 forms the well-established trimolecular complex (MT1-MMP/TIMP-2/MMP-2) for further TIMP-2-dependent autocatalytic cleavage to the fully active species. This alternate mechanism may supplement the traditional TIMP-2-mediated first step mechanism.
St. Vincent's Institute of Medical Research, 29 Regent Street, Fitzroy, Vic. 3065, Australia.
Marc A
MA
Lafleur
Angus M
AM
Tester
Erik W
EW
Thompson
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018093:Gelatinases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; C507096:Mmp14 protein, mouse; D011994:Recombinant Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14