Thrombin-thrombomodulin activation of protein C facilitates the activation of progelatinase A.
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.
Pekovich
S R
SR
Department of Pathology, C-3321 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bock
P E
PE
Hoover
R L
RL
D002460:Cell Line; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D011486:Protein C / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*; D018180:Thrombomodulin / Q000378:metabolism*
D004792:Enzyme Precursors; D011486:Protein C; D018180:Thrombomodulin; D013917:Thrombin; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase