PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation

Giordano Pula, Kai Schuh, Keiko Nakayama, Keiichi Nakayama, Ulrich Walter, Alastair W. Poole

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Protein kinase Cδ (PKCδ) 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 PKCδ-/- platelets, we show that the mechanism did not involve altered inside-out signaling to integrin α IIbβ3 and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLCγ2 between wild-type and PKCδ-/- 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 PKCδ-/- 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 PKCδ is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKCδ 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. PKCδ is therefore a critical negative regulator of filopodia, and hence platelet aggregation, through a functional interaction with the actin organizer VASP.

Original languageEnglish
Pages (from-to)4035-4044
Number of pages10
JournalBlood
Volume108
Issue number13
DOIs
Publication statusPublished - Dec 15 2006

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Pseudopodia
Platelets
Platelet Aggregation
Protein Kinase C
Collagen
Blood Platelets
Agglomeration
Actins
Phosphorylation
vasodilator-stimulated phosphoprotein
Actin Cytoskeleton
Integrins
Polymerization
Adhesives
Tyrosine
Adhesion

All Science Journal Classification (ASJC) codes

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. / Pula, Giordano; Schuh, Kai; Nakayama, Keiko; Nakayama, Keiichi; Walter, Ulrich; Poole, Alastair W.

In: Blood, Vol. 108, No. 13, 15.12.2006, p. 4035-4044.

Research output: Contribution to journalArticle

Pula, Giordano ; Schuh, Kai ; Nakayama, Keiko ; Nakayama, Keiichi ; Walter, Ulrich ; Poole, Alastair W. / PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. In: Blood. 2006 ; Vol. 108, No. 13. pp. 4035-4044.
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