ABSTRACT
Members of the protein kinase C (PKC) family of serine/threonine kinases have been implicated in several physiological processes regulating the activation response of platelets. They are involved in processes leading to granule secretion, integrin activation, platelet aggregation and spreading, and procoagulation. The protein kinase C θ (PKCθ) isoform, which was originally identified in T lymphocytes, is also expressed at relatively high levels in platelets, wherein it is involved in the regulation of hemostasis and thrombosis. Recent studies suggest a role for PKCθ in protease-activated receptor (PAR)-, glycoprotein VI (GPVI) receptor- and glycoprotein α(IIb)ß(3) integrin receptor-linked signal transduction pathways. The present review focuses on the latest observations relevant to the role of PKCθ in platelet activation.
Subject(s)
Blood Platelets/enzymology , Isoenzymes/metabolism , Platelet Aggregation/physiology , Protein Kinase C/metabolism , Animals , Gene Expression Regulation, Enzymologic/physiology , Hemostasis/physiology , Humans , Isoenzymes/genetics , Platelet Glycoprotein GPIIb-IIIa Complex/genetics , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Protein Kinase C/genetics , Protein Kinase C-theta , Receptors, Thrombin/genetics , Receptors, Thrombin/metabolism , Secretory Vesicles/enzymology , Secretory Vesicles/genetics , Signal Transduction/physiology , T-Lymphocytes/enzymology , Thrombosis/enzymology , Thrombosis/geneticsABSTRACT
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.
