Blood Journal
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Brief report
Genetic evidence for a predominant role of PI3Kβ catalytic activity in ITAM- and integrin-mediated signaling in platelets

  1. Ilaria Canobbio1,*,
  2. Lucia Stefanini1,*,
  3. Lina Cipolla1,
  4. Elisa Ciraolo2,
  5. Cristian Gruppi1,
  6. Cesare Balduini1,
  7. Emilio Hirsch2,, and
  8. Mauro Torti1,
  1. 1Department of Biochemistry, University of Pavia, Pavia; and
  2. 2Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy

Abstract

Phosphatidylinositol 3-kinase (PI3K) isoforms PI3Kβ and PI3Kγ are implicated in platelet adhesion, activation, and aggregation, but their relative contribution is still unclear or controversial. Here, we report the first comparative functional analysis of platelets from mice expressing a catalytically inactive form of PI3Kβ or PI3Kγ. We demonstrate that both isoforms were similarly required for maximal activation of the small GTPase Rap1b and for complete platelet aggregation upon stimulation of G protein–coupled receptors for adenosine 5′-diphosphate (ADP) or U46619. Their contribution to these events, however, was largely redundant and dispensable. However, PI3Kβ, but not PI3Kγ, enzymatic activity was absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream of the immunoreceptor tyrosine-based activation motif (ITAM)–bearing receptor glycoprotein VI (GPVI). Moreover, PI3Kβ was a major essential regulator of platelet adhesion to fibrinogen and of integrin αIIbβ3-mediated spreading. These results provide genetic evidence for a crucial and selective role of PI3Kβ in signaling through GPVI and integrin αIIbβ3.

  • Submitted March 2, 2009.
  • Accepted May 29, 2009.
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