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Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function
Spencer W Galt1, Stephan Lindemann, Loren Allen
1Departments of Vascular Surgery, Internal Medicine, Program in Human Molecular Genetics, University of Utah, Salt Lake City, USA. sgalt@hsc.utah.edu
Abstract:
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.
Insights
Matrix metalloproteinases (MMPs), specifically MMP-1, act as signaling molecules in platelets. This enzyme regulates platelet aggregation and intracellular signaling, revealing a novel role in thrombotic events.
Area of Science:
- Biochemistry
- Cell Biology
- Hematology
Background:
- Matrix metalloproteinases (MMPs) are enzymes involved in extracellular matrix remodeling.
- Evidence for MMPs acting as signaling molecules is limited.
- Platelets play a crucial role in hemostasis and thrombosis.
Purpose of the Study:
- To investigate the signaling capacity of matrix metalloproteinases (MMPs) in platelets.
- To determine the role of MMP-1 in platelet activation and aggregation.
Main Methods:
- Treatment of platelets with exogenous MMP-1 (interstitial collagenase).
- Analysis of protein tyrosine phosphorylation and beta(3) integrin localization.
- Assessment of platelet aggregation using MMP inhibitors and blocking antibodies.
Main Results:
- Exogenous MMP-1 increased tyrosine-phosphorylated proteins and beta(3) integrin targeting in platelets.
- Activated platelets process latent MMP-1 into its active form.
- Inhibition of MMP-1 activity attenuated platelet phosphorylation, integrin movement, and aggregation.
Conclusions:
- MMP-1 functions as a signaling molecule in platelets, regulating key aspects of platelet activation.
- MMP-1 activation within platelets plays a critical role in controlling thrombotic events.
- These findings identify a novel signaling pathway involving MMPs in platelet function.