Abstract
The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKCδ, but not PKCα or PKCβ, is required for collagen-induced phospholipase C-dependent signaling, activation of α<sub>IIb</sub>β<sub>3</sub>, and platelet aggregation. Analysis of PKCδ phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by α<sub>IIb</sub>β<sub>3</sub> outside-in signaling. Moreover, PKCδ triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A<sub>2</sub>, which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKCδ signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A<sub>2</sub>.
Highlights
Platelet adhesion represents the first step in thrombogenesis
Even though protein kinase C (PKC) share a high degree of homology, it is believed that particular PKC isoforms have unique and specific functions within different cell types [24]
It is well established that collagen-induced platelet activation and aggregation through GPVI is mediated by tyrosine kinase Syk and activation of PLC␥2 [32, 33], there is limited information concerning the roles of specific PKC isoforms and their downstream effectors in this process
Summary
Platelet adhesion represents the first step in thrombogenesis. The initial binding of platelets to damaged blood vessels, which does not necessitate activation, is predominantly mediated by the interactions of platelet glycoprotein (GP)2 Ib-IX-V (leucinrich) with von Willebrand Factor [6] at high shear and ␣21. PKC␦ in Platelet Function shows that PKC␦ is positively regulated by ␣IIb3 outside-in signaling and is involved in the release of TxA2 through the MEK/ERK and p38 MAPK signaling pathways, which is required for collagen-induced but not thrombin-induced platelet activation and aggregation.
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