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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4035-4044.
Prepublished online as a Blood First Edition Paper on August 29, 2006; DOI 10.1182/blood-2006-05-023739.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
PKC regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation
Giordano Pula,
Kai Schuh,
Keiko Nakayama,
Keiichi I. Nakayama,
Ulrich Walter, and
Alastair W. Poole
From the Department of Pharmacology, School of Medical Sciences, University of Bristol, United Kingdom; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany; Division of Developmental Genetics, Tohoku University, Sendai Miyagi, Japan; and Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Protein kinase C (PKC) 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–/– platelets, we show that the mechanism did not involve altered inside-out signaling to integrin  IIb 3 and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLC 2 between wild-type and PKC–/– 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 filopodia generation in PKC–/– 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 is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKC 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 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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