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Selective involvement of TIMP‐2 in the second activational cleavage of pro‐MMP‐2: refinement of the pro‐MMP‐2 activation mechanism
Author(s) -
Lafleur Marc A,
Tester Angus M,
Thompson Erik W
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)01094-9
Subject(s) - matrix metalloproteinase , cleavage (geology) , hemopexin , chemistry , transfection , microbiology and biotechnology , mechanism (biology) , matrilysin , biophysics , metalloproteinase , biochemistry , enzyme , biology , gene , paleontology , heme , philosophy , epistemology , fracture (geology)
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.