Essential role of protein kinase Cδ in platelet signaling αIIbβ3 activation, and thromboxane A2 release

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 PKC delta, but not PKC alpha or PKC beta, is required for collagen-induced phospholipase C-dependent signaling, activation of alpha(IIb)beta(3), and platelet aggregation. Analysis of PKC delta phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by alpha(IIb)beta(3) outside-in signaling. Moreover, PKC delta triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extra cellular signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A(2), 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 PKC delta signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A(2).