Stimulation of mTORC2 by integrin αIIbβ3 is required for PI3Kβ-dependent activation of Akt but is dispensable for platelet spreading on fibrinogen

M. Torti, D. Manganaro, C. Visconte, M. Zarà, J. Canino, M. Vismara, I. Canobbio, G.F. Guidetti

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphatidylinositol 3 kinase (PI3K) is a major player in platelet activation and regulates thrombus formation and stabilization. The β isoform of PI3K is implicated in integrin αIIbβ3 outside-in signaling, is required for the phosphorylation of Akt, and controls efficient platelet spreading upon adhesion to fibrinogen. In this study we found that during integrin αIIbβ3 outside-in signaling PI3Kβ-dependent phosphorylation of Akt on Serine473 is mediated by the mammalian target of rapamycin complex 2 (mTORC2). The activity of mTORC2 is stimulated upon platelet adhesion to fibrinogen, as documented by increased autophosphorylation. However, mTORC2 activation downstream of integrin αIIbβ3 is PI3Kβ-independent. Inhibition of mTORC2, but not mTORC1, also prevents Akt phosphorylation of Threonine308 and affects Akt activity, resulting in the inhibition of GSK3α/β phosphorylation. Nevertheless, mTORC2 or Akt inhibition does not alter PI3Kβ-dependent platelet spreading on fibrinogen. The activation of the small GTPase Rap1b downstream of integrin αIIbβ3 is regulated by PI3Kβ but is not affected upon inhibition of either mTORC2 or Akt. Altogether, these results demonstrate for the first time the activation of mTORC2 and its involvement in Akt phosphorylation and stimulation during integrin αIIbβ3 outside-in signaling. Moreover, the results demonstrate that the mTORC2/Akt pathway is dispensable for PI3Kβ-regulated platelet spreading on fibrinogen. © 2019, © 2019 Taylor & Francis Group, LLC.
Original languageEnglish
Pages (from-to)521-529
Number of pages9
JournalPlatelets
Volume31
Issue number4
DOIs
Publication statusPublished - 2020

Keywords

  • Akt
  • integrins
  • mTOR
  • PI3K
  • platelet spreading
  • Rap1
  • 2 (4 amino 1 isopropyl 1h pyrazolo[3,4 d]pyrimidin 3 yl) 1h indol 5 ol
  • 5 [2 (2,6 dimethylmorpholino) 4 morpholinopyrido[2,3 d]pyrimidin 7 yl] 2 methoxybenzenemethanol
  • 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one
  • alpha integrin
  • azd 8055
  • fibrinogen
  • integrin alphaiibbeta3
  • mammalian target of rapamycin complex 2
  • phosphatidylinositol 3 kinase
  • protein kinase B
  • rapamycin
  • serine
  • threonine
  • unclassified drug
  • fibrinogen receptor
  • glycogen synthase kinase 3
  • glycogen synthase kinase 3alpha
  • glycogen synthase kinase 3beta
  • GSK3B protein, human
  • Rap protein
  • RAP1B protein, human
  • Article
  • autophosphorylation
  • comparative study
  • controlled study
  • human
  • human cell
  • priority journal
  • protein phosphorylation
  • signal transduction
  • thrombocyte adhesion
  • drug effect
  • enzymology
  • genetics
  • metabolism
  • phosphorylation
  • physiology
  • thrombocyte
  • Blood Platelets
  • Fibrinogen
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mechanistic Target of Rapamycin Complex 2
  • Phosphatidylinositol 3-Kinase
  • Phosphorylation
  • Platelet Adhesiveness
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Proto-Oncogene Proteins c-akt
  • rap GTP-Binding Proteins
  • Signal Transduction
  • Sirolimus

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