Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 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 PKCdelta, but not PKCalpha or PKCbeta, is required for collagen-induced phospholipase C-dependent signaling, activation of alpha(IIb)beta(3), and platelet aggregation. Analysis of PKCdelta 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, PKCdelta 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(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 PKCdelta signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A(2).
Yacoub
Daniel
D
Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec H1T 1C8, Canada.
Théorêt
Jean-François
JF
Villeneuve
Louis
L
Abou-Saleh
Haissam
H
Mourad
Walid
W
Allen
Bruce G
BG
Merhi
Yahye
Y
D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism* / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000096:biosynthesis / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013928:Thromboxane A2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D021122:Protein Subunits; D013928:Thromboxane A2; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases