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Keywords:

  • Bruton's tyrosine kinase;
  • fibrinogen;
  • integrins;
  • platelets;
  • protein kinase C

Summary.  Fibrinogen binding to platelets triggers αIIbβ3-dependent outside-in signals that promote actin rearrangements and cell spreading. Studies with chemical inhibitors or activators have implicated protein kinase C (PKC) in αIIbβ3 function. However, the role of individual PKC isoforms is poorly understood. Biochemical and genetic approaches were used to determine whether PKCθ is involved in αIIbβ3 signaling. PKCθ was constitutively associated with αIIbβ3 in human and murine platelets. Fibrinogen binding to αIIbβ3 stimulated the association of PKCθ with tyrosine kinases Btk and Syk, and tyrosine phosphorylation of PKCθ, Btk and the actin regulator, Wiskott-Aldrich syndrome protein (WASP). Mouse platelets deficient in PKCθ or Btk failed to spread on fibrinogen. Furthermore, PKCθ was required for phosphorylation of WASP-interacting protein on Ser-488, an event that has been linked to WASP activation of the Arp2/3 complex and actin polymerization in lymphocytes. Neither PKCθ nor Btk were required for agonist-induced inside-out signaling and fibrinogen binding to αIIbβ3. Thus, PKCθ is a newly identified, essential member of a dynamic outside-in signaling complex that includes Btk and that couples αIIbβ3 to the actin cytoskeleton.