Published online before print April 25, 2002, doi: 10.1161/01.RES.0000019241.12929.EB
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Submitted on March 7, 2002
Revised on April 8, 2002
Accepted on April 11, 2002
Outside-In Signals Delivered by Matrix Metalloproteinase-1 Regulate Platelet Function
Spencer W. Galt *;
From the Departments of Vascular Surgery (S.W.G., L.W.K.), Internal Medicine (T.M.M., S.M.P., G.A.Z., A.S.W.), and Pathology (T.M.M.) and the Program in Human Molecular Genetics (S.L., L.A., D.Z.M., J.M.F., T.M.M., G.A.Z., A.S.W.), University of Utah, Salt Lake City.
* To whom correspondence should be addressed. E-mail: sgalt{at}hsc.utah.edu and andy.weyrich@hmbg.utah.edu.
Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix proteins. These enzymes are implicated in a variety of physiological and pathological events characterized by extracellular matrix remodeling. Recent studies suggest that MMPs may have a signaling capacity, but direct evidence supporting this concept is lacking. In the present study, we demonstrate that outside-in signals delivered by exogenous MMP-1 (interstitial collagenase) markedly increase the number of tyrosine-phosphorylated proteins in platelets. Active MMP-1 also targets ß3 integrins to areas of cell contact and primes platelets for aggregation. Examination of the endogenous enzyme demonstrated that activated platelets process latent MMP-1 into its active form. Neutralization of MMP-1 activity with MMP inhibitors or specific blocking antibodies markedly attenuates agonist-induced phosphorylation of intracellular proteins, movement of ß3 integrins to cell contact points, and intercellular aggregation. The finding that MMP-1 is rapidly activated in platelets and controls functional responses identifies a new role for this metalloproteinase as a signaling molecule that regulates thrombotic events.
Key words: matrix metalloproteinases • platelets • signaling • thrombosis
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