Journal
BLOOD
Volume 108, Issue 13, Pages 4035-4044Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-05-023739
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Funding
- Medical Research Council [G9721484] Funding Source: researchfish
- Medical Research Council [G9721484] Funding Source: Medline
- Wellcome Trust [069572] Funding Source: Medline
- MRC [G9721484] Funding Source: UKRI
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Protein kinase C delta (PKC delta) has been shown by pharmacologic approaches to negatively regulate collagen-induced platelet aggregation. Here we addressed the molecular and cellular mechanisms underlying this negative regulation. Using PKC delta-/- platelets, we show that the mechanism did not involve altered inside-out signaling to integrin alpha(llb)beta(3) and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLC gamma 2 between wild-type and PKC delta-/- platelets. There was also no increase in secretion of dense granule content, in contrast to studies using rottlerin where secretion was enhanced. Importantly, however, there was marked enhancement of flopodia generation in PKC delta-/- platelets upon adhesion to collagen compared with wild-type platelets. Filopodia play an essential role regulating adhesive events leading to platelet aggregation by increasing platelet-platelet contact. We show that the critical effector for PKC delta is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKC delta physically interacts with VASP constitutively and regulates its phosphorylation on Ser157. In VASP(-/-) platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated. PKC delta is therefore a critical negative regulator of filopodia, and hence platelet aggregation, through a functional interaction with the actin organizer VASP.
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