Outside-In Signals Delivered by Matrix Metalloproteinase-1 Regulate Platelet Function

• Published in: Circulation research 2002-05, Vol.90 (10), p.1093-1099
• Main Authors: Galt, Spencer W, Lindemann, Stephan, Allen, Loren, Medd, Donald J, Falk, Jeanne M, McIntyre, Thomas M, Prescott, Stephen M, Kraiss, Larry W, Zimmerman, Guy A, Weyrich, Andrew S
• Format: Article
• Language: English
• Subjects: Antigens, CD - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Blood Platelets - drug effects; Blood Platelets - enzymology; Blood Platelets - physiology; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Humans; Integrin beta3; Matrix Metalloproteinase 1 - pharmacology; Matrix Metalloproteinase 1 - physiology; Matrix Metalloproteinase Inhibitors; Medical sciences; Phosphorylation; Platelet Activation; Platelet Aggregation; Platelet Membrane Glycoproteins - metabolism; Protease Inhibitors - pharmacology; Proteins - metabolism; Signal Transduction
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000019241.12929.EB

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 β3 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 β3 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.