PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling

Nat Commun. 2015 Jun 23;6:7400. doi: 10.1038/ncomms8400.

Abstract

In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes and whether isoform-selective interplays exist is currently unclear. Here we report that insulin signalling triggers the association of the liver-specific class II PI3K isoform γ (PI3K-C2γ) with Rab5-GTP, and its recruitment to Rab5-positive early endosomes. In these vesicles, PI3K-C2γ produces a phosphatidylinositol-3,4-bisphosphate pool specifically required for delayed and sustained endosomal Akt2 stimulation. Accordingly, loss of PI3K-C2γ does not affect insulin-dependent Akt1 activation as well as S6K and FoxO1-3 phosphorylation, but selectively reduces Akt2 activation, which specifically inhibits glycogen synthase activity. As a consequence, PI3K-C2γ-deficient mice display severely reduced liver accumulation of glycogen and develop hyperlipidemia, adiposity as well as insulin resistance with age or after consumption of a high-fat diet. Our data indicate PI3K-C2γ supports an isoenzyme-specific forking of insulin-mediated signal transduction to an endosomal pool of Akt2, required for glucose homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / genetics
  • Aging / genetics*
  • Animals
  • Diet, High-Fat
  • Endosomes / metabolism
  • Forkhead Transcription Factors / metabolism
  • Glucose / metabolism
  • Glycogen / metabolism*
  • Glycogen Synthase / metabolism
  • Hepatocytes / metabolism*
  • Homeostasis
  • Hyperlipidemias / genetics
  • Insulin / metabolism*
  • Insulin Resistance / genetics
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction
  • rab5 GTP-Binding Proteins / metabolism*

Substances

  • Forkhead Transcription Factors
  • Insulin
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4-diphosphate
  • Glycogen
  • Glycogen Synthase
  • Phosphatidylinositol 3-Kinases
  • Pik3c2g protein, mouse
  • Akt1 protein, mouse
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • rab5 GTP-Binding Proteins
  • Glucose