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

Journal article
Authors Angela Molinaro
Barbara Becattini
Arianna Mazzoli
Augusto Bleve
Lucia Radici
Ingela Maxvall
Victoria Rotter Sopasakis
Antonio Molinaro
Fredrik Bäckhed
Giovanni Solinas
Published in Cell Metabolism
Volume 29
Issue 6
Pages 1400-+
ISSN 1550-4131
Publication year 2019
Published at Wallenberg Laboratory
Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 1400-+
Language en
Links dx.doi.org/10.1016/j.cmet.2019.03.0...
https://www.sciencedirect.com/scien...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Nutrition and Dietetics, Endocrinology and Diabetes, Cancer and Oncology, Cell biology, Physiology, Medicinal Chemistry, Pharmaceutical Sciences

Abstract

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 be dosed below their hyperglycemic threshold to achieve isoform selectivity.

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