Abstract
BackgroundIncreasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation.Methodology/Principal FindingsIn this study, we focus on the role of two novel PKC isoforms, PKCδ and PKCε, in both mouse and human platelets. PKCδ is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKCδ undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKCε, is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKCε in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcRγ-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor.ConclusionsThese results demonstrate a reciprocal relationship in levels of the novel PKC isoforms δ and ε in human and mouse platelets and a selective role for PKCε in signalling through GPVI.
Highlights
The major receptors which induce platelet activation signal by different mechanisms many converge on the activation of the protein kinase C (PKC) family of serine/threonine kinases
These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms d and e in human and mouse platelets and a selective role for PKCe in signalling through GPVI
PKCh is tyrosine phosphorylated in human platelets in response to collagen, the snake toxin Alboaggregin A and downstream of aIIbb3 [14,15]
Summary
The major receptors which induce platelet activation signal by different mechanisms many converge on the activation of the protein kinase C (PKC) family of serine/threonine kinases. Initial evidence for the involvement of the novel PKC isoforms in platelet activation came from studies monitoring tyrosine phosphorylation of these proteins following stimulation of human platelets. PKCd is tyrosine phosphorylated at two distinct sites, Tyr311 and 565, in response to activation of GPVI and PAR receptors, but not by the major platelet integrin, aIIbb3 [10,11,12,13]. This provides a potential mechanism for both direct regulation of PKCd activity and in initiating downstream signalling through recruitment of SH2 domain containing proteins. Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation
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