Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site.
Matrix metalloproteases (MMPs) play important roles in normal and pathological remodeling processes including atherothrombotic disease, inflammation, angiogenesis, and cancer. MMPs have been viewed as matrix-degrading enzymes, but recent studies have shown that they possess direct signaling capabilities. Platelets harbor several MMPs that modulate hemostatic function and platelet survival; however their mode of action remains unknown. We show that platelet MMP-1 activates protease-activated receptor-1 (PAR1) on the surface of platelets. Exposure of platelets to fibrillar collagen converts the surface-bound proMMP-1 zymogen to active MMP-1, which promotes aggregation through PAR1. Unexpectedly, MMP-1 cleaves PAR1 at a distinct site that strongly activates Rho-GTP pathways, cell shape change and motility, and MAPK signaling. Blockade of MMP1-PAR1 curtails thrombogenesis under arterial flow conditions and inhibits thrombosis in animals. These studies provide a link between matrix-dependent activation of metalloproteases and platelet-G protein signaling and identify MMP1-PAR1 as a potential target for the prevention of arterial thrombosis.
Trivedi
Vishal
V
Department of Medicine, Tufts University School of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
Boire
Adrienne
A
Tchernychev
Boris
B
Kaneider
Nicole C
NC
Leger
Andrew J
AJ
O'Callaghan
Katie
K
Covic
Lidija
L
Kuliopulos
Athan
A
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044463:Receptor, PAR-1 / Q000737:chemistry / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008024:Ligands; D044463:Receptor, PAR-1; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D019204:GTP-Binding Proteins