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  • Molinaro, AngelaGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine (author)

Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS.

  • Article/chapterEnglish2019

Publisher, publication year, extent ...

  • Elsevier BV,2019

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/279854
  • https://gup.ub.gu.se/publication/279854URI
  • https://doi.org/10.1016/j.cmet.2019.03.010DOI

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  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should bedosed below their hyperglycemic threshold to achieve isoform selectivity.

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  • Becattini, BarbaraGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory(Swepub:gu)xbecba (author)
  • Mazzoli, AriannaGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory (author)
  • Bleve, AugustoGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine (author)
  • Radici, LuciaGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory (author)
  • Maxvall, Ingela (author)
  • Rotter Sopasakis, Victoria,1972Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Wallenberglaboratoriet,Institute of Biomedicine,Wallenberg Laboratory(Swepub:gu)xrotvi (author)
  • Molinaro, AntonioGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xmolia (author)
  • Bäckhed, Fredrik,1973Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory(Swepub:gu)xbafre (author)
  • Solinas, GiovanniGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xsolgi (author)
  • Göteborgs universitetWallenberglaboratoriet (creator_code:org_t)

Related titles

  • In:Cell Metabolism: Elsevier BV29:61550-41311932-7420

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