Phosphoinositide 3-kinases p110α and p110β have differential roles in insulin-like growth factor-1-mediated Akt phosphorylation and platelet priming

Thomas A Blair, Samantha F Moore, Christopher M Williams, Alastair W Poole, Bart Vanhaesebroeck, Ingeborg Hers

Research output: Contribution to journalArticle (Academic Journal)peer-review

31 Citations (Scopus)


OBJECTIVE: Platelet hyperactivity is a contributing factor in the pathogenesis of cardiovascular disease and can be induced by elevated levels of circulating growth factors, such as insulin-like growth factor-1 (IGF-1). IGF-1 is a primer that cannot stimulate platelet activation by itself, but in combination with physiological stimuli can potentiate platelet functional responses via a phosphoinositide 3-kinase-dependent mechanism. In this study, we explored the role of the phosphoinositide 3-kinase p110α isoform in IGF-1-mediated enhancement of platelet function.

APPROACH AND RESULTS: Using a platelet-specific p110α knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110α, did not affect proteinase-activated receptor 4 signaling to Akt/protein kinase B but significantly reduced IGF-1-mediated Akt phosphorylation. The p110β inhibitor TGX-221 abolished IGF-1-induced Akt phosphorylation in p110α-deficient platelets, demonstrating that both p110α and p110β contribute to IGF-1-mediated Akt phosphorylation. Genetic deletion of p110α had no effect on IGF-1-mediated increases in thrombus formation on collagen and enhancement of proteinase-activated receptor 4-mediated integrin activation and α-granule secretion. In contrast, pharmacological inhibition of p110α blocked IGF-1-mediated potentiation of integrin activation and α-granule secretion. Functional enhancement by IGF-1 in p110α knockout samples was lost after TGX-221 treatment, suggesting that p110β drives priming in the absence of the p110α isoform.

CONCLUSIONS: Together, these results demonstrate that both p110α and p110β are involved in Akt signaling by IGF-1, but that it is the p110α isoform that is responsible for IGF-1-mediated potentiation of platelet function.

Original languageEnglish
Pages (from-to)1681-8
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number8
Publication statusPublished - Aug 2014


  • Animals
  • Blood Platelets
  • Insulin-Like Growth Factor I
  • Integrin alpha2
  • Integrin beta3
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Platelet Activation
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Receptors, Thrombin
  • Secretory Vesicles
  • Signal Transduction
  • Thrombosis
  • Time Factors


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