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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. This Article Full Text (PDF) Supplemental Figures and Videos All Versions of this Article: blood-2006-05-023739v1 108/13/4035    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pula, G. Articles by Poole, A. W. Search for Related Content PubMed PubMed Citation Articles by Pula, G. Articles by Poole, A. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 17, 2006 Accepted August 4, 2006 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* University of Bristol, UK Institute for Clinical Biochemistry, Wuerzburg, Germany Tohoku University, Japan Kyushu University, Japan * Corresponding author; email: a.poole{at}bris.ac.uk. Protein kinase C (PKC) has been shown by pharmacological 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 IIb3 and did not affect early signaling events downstream of GP VI, since there was no difference in tyrosine phosphorylation of PLC2 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 to 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 polymerisation 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Uncovering the dark side of PKC Ulhas P. Naik Blood 2006 108: 3959-3960. [Full Text] [PDF] This article has been cited by other articles: P. M. Benz, C. Blume, S. Seifert, S. Wilhelm, J. Waschke, K. Schuh, F. Gertler, T. Munzel, and T. Renne Differential VASP phosphorylation controls remodeling of the actin cytoskeleton J. Cell Sci., November 1, 2009; 122(21): 3954 - 3965. [Abstract] [Full Text] [PDF] U. P. Naik Lyn and PKC{delta} order SHIP1 embargo Blood, October 1, 2009; 114(14): 2856 - 2857. [Full Text] [PDF] N. F. Neel, M. Barzik, D. Raman, T. Sobolik-Delmaire, J. Sai, A. J. Ham, R. L. Mernaugh, F. B. Gertler, and A. Richmond VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis J. Cell Sci., June 1, 2009; 122(11): 1882 - 1894. [Abstract] [Full Text] [PDF] R. Chari, T. Getz, B. Nagy Jr, K. Bhavaraju, Y. Mao, Y. S. Bynagari, S. Murugappan, K. Nakayama, and S. P. Kunapuli Protein Kinase C{delta} Differentially Regulates Platelet Functional Responses Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 699 - 705. [Abstract] [Full Text] [PDF]

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