PKCtheta is required for hemostasis and positive regulation of thrombin-induced platelet aggregation and alpha-granule secretion.
Platelet activation due to vascular injury is essential for hemostatic plug formation, and is mediated by agonists, such as thrombin, which trigger distinct receptor-coupled signaling pathways. Thrombin is a coagulation protease, which activates G protein-coupled protease-activated receptors (PARs) on the surface of platelets. We found that C57BL/6J and BALB/C mice that are deficient in protein kinase C theta (PKCtheta), exhibit an impaired hemostasis, and prolonged bleeding following vascular injury. In addition, murine platelets deficient in PKCtheta displayed an impaired thrombin-induced platelet activation and aggregation response. Lack of PKCtheta also resulted in impaired alpha-granule secretion, as demonstrated by the low surface expression of CD62P, in thrombin-stimulated platelets. Since PAR4 is the only mouse PAR receptor that delivers thrombin-induced activation signals in platelets, our results suggest that PKCtheta is a critical effector molecule in the PAR4-linked signaling pathways and in the regulation of normal hemostasis in mice.
Cohen
Sagit
S
The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and The Cancer Research Center, Ben Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel.
Braiman
Alex
A
Shubinsky
George
G
Ohayon
Ariel
A
Altman
Amnon
A
Isakov
Noah
N
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000502:physiology; D006487:Hemostasis / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D019007:P-Selectin / Q000378:metabolism; D010974:Platelet Aggregation / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D013917:Thrombin / Q000378:metabolism*
D007527:Isoenzymes; D019007:P-Selectin; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D013917:Thrombin