Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation.
Platelet activation is a complex balance of positive and negative signaling pathways. The protein kinase C (PKC) family is a major regulator of platelet granule secretion, integrin activation, aggregation, spreading and procoagulant activity. As broad-spectrum PKC inhibitors reduce secretion and aggregation, the PKC family is generally considered to be a positive regulator of platelet activation. However, the individual members of the PKC family that are expressed in platelets are regulated in different ways, and an increasing body of evidence indicates that they have distinct, and often opposing, roles. Many of the recent advances in understanding the contributions of individual PKC isoforms have come from mouse gene knockout studies. PKCalpha, a classic isoform, is an essential positive regulator of granule secretion and thrombus formation, both in vitro and in vivo. Mice lacking PKCalpha show much reduced thrombus formation in vivo but do not have a bleeding defect, suggesting that PKCalpha could be an attractive antithrombotic target. Important, apparently non-redundant, roles, both positive and negative, for the novel PKC isoforms delta, theta and epsilon in granule secretion have also been proposed, indicating highly complex regulation of this essential process. Similarly, PKCbeta, PKCdelta and PKCtheta have non-redundant roles in platelet spreading, as absence of either PKCbeta or PKCtheta reduces spreading, whereas PKCdelta negatively regulates filopodial formation. This negative signaling by PKCdelta may reduce platelet aggregation and so restrict thrombus formation. In this review, we discuss the current understanding of the regulation and functions of individual PKC isoforms in platelet activation and thrombus formation.
Harper
M T
MT
Department of Physiology and Pharmacology, University of Bristol, Bristol, UK.
Poole
A W
AW
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D003594:Cytoplasmic Granules / Q000201:enzymology; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000235:genetics; D010974:Platelet Aggregation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D013931:Thromboxanes / Q000378:metabolism
D007527:Isoenzymes; D013931:Thromboxanes; D011493:Protein Kinase C