Thrombin-thrombomodulin activation of protein C facilitates the activationof 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 implic ated in disease states such as cancer and atherosclerosis, Activation of MM P-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 metalloproteinas e generates an intermediate, A secondary cleavage and activation of the int ermediate is thought to occur autocatalytically. Previous studies have show n that thrombin can also activate progelatinase A in the presence of endoth elial cells, We show that this cell-dependent mechanism of MMP-2 activation also occurs with THP-I cells and involves binding of thrombin to thrombomo dulin present on the cell surface and generation of the anti-coagulant prot ein, activated protein C, We demonstrate that activated protein C is direct ly 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 an d anti-coagulation. (C) 2001 Published by Elsevier Science B,V, on behalf o f the Federation of European Biochemical Societies.