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Thrombin–thrombomodulin activation of protein C facilitates the activation of progelatinase A
Author(s) -
Pekovich Stevan R,
Bock Paul E,
Hoover Richard L
Publication year - 2001
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(01)02296-7
Subject(s) - thrombomodulin , thrombin , chemistry , thrombin generation , coagulation , protein c , microbiology and biotechnology , biophysics , biochemistry , medicine , biology , platelet
The activation of the matrix metalloproteinase progelatinase A (MMP‐2) has been of keen interest because an increase in MMP‐2 activity has been implicated in disease states such as cancer and atherosclerosis. Activation of MMP‐2 occurs on the surface of specific cell types in two steps. In the first step, primary cleavage of MMP‐2 by a membrane‐type matrix metalloproteinase generates an intermediate. A secondary cleavage and activation of the intermediate is thought to occur autocatalytically. Previous studies have shown that thrombin can also activate progelatinase A in the presence of endothelial cells. We show that this cell‐dependent mechanism of MMP‐2 activation also occurs with THP‐1 cells and involves binding of thrombin to thrombomodulin present on the cell surface and generation of the anti‐coagulant protein, activated protein C. We demonstrate that activated protein C is directly responsible for activation and cleavage of the gelatinase A intermediate. This work contributes new mechanistic insights into the activation of MMP‐2 and provides a novel link between matrix metalloproteinase activation and anti‐coagulation.