PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism

Cell Rep. 2019 May 14;27(7):1991-2001.e5. doi: 10.1016/j.celrep.2019.04.070.

Abstract

Insulin stimulates the conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), which mediates downstream cellular responses. PI(4,5)P2 is produced by phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and by phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Here, we show that the loss of PIP4Ks (PIP4K2A, PIP4K2B, and PIP4K2C) in vitro results in a paradoxical increase in PI(4,5)P2 and a concomitant increase in insulin-stimulated production of PI(3,4,5)P3. The reintroduction of either wild-type or kinase-dead mutants of the PIP4Ks restored cellular PI(4,5)P2 levels and insulin stimulation of the PI3K pathway, suggesting a catalytic-independent role of PIP4Ks in regulating PI(4,5)P2 levels. These effects are explained by an increase in PIP5K activity upon the deletion of PIP4Ks, which normally suppresses PIP5K activity through a direct binding interaction mediated by the N-terminal motif VMLΦPDD of PIP4K. Our work uncovers an allosteric function of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P2 synthesis and insulin-dependent conversion to PI(3,4,5)P3 and suggests that the pharmacological depletion of PIP4K enzymes could represent a strategy for enhancing insulin signaling.

Keywords: Akt; PI(3,4,5)P(3); PI(4,5)P(2); PI3K; PI5P4K; PIP4K; PIP5K; RTK; insulin; signaling.

Publication types

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

MeSH terms

  • Animals
  • Humans
  • Insulin / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / genetics
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Signal Transduction*

Substances

  • Insulin
  • Phosphatidylinositol 4,5-Diphosphate
  • PIP4K2A protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • PIP4K2C protein, human