Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function.
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 beta(3) 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 beta(3) 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.
Galt
Spencer W
SW
Departments of Vascular Surgery, Internal Medicine, Program in Human Molecular Genetics, University of Utah, Salt Lake City, USA. sgalt@hsc.utah.edu
Lindemann
Stephan
S
Allen
Loren
L
Medd
Donald J
DJ
Falk
Jeanne M
JM
McIntyre
Thomas M
TM
Prescott
Stephen M
SM
Kraiss
Larry W
LW
Zimmerman
Guy A
GA
Weyrich
Andrew S
AS
D015703:Antigens, CD / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D006801:Humans; D039661:Integrin beta3; D020781:Matrix Metalloproteinase 1 / Q000494:pharmacology / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction
D015703:Antigens, CD; D039661:Integrin beta3; D061965:Matrix Metalloproteinase Inhibitors; D010980:Platelet Membrane Glycoproteins; D011480:Protease Inhibitors; D011506:Proteins; D020781:Matrix Metalloproteinase 1