Phosphatidylinositol 5 Phosphate 4-Kinase Regulates Plasma-Membrane PIP 3 Turnover and Insulin Signaling

Cell Rep. 2019 May 14;27(7):1979-1990.e7. doi: 10.1016/j.celrep.2019.04.084.

Abstract

Phosphatidylinositol 3,4,5-trisphosphate (PIP3) generation at the plasma membrane is a key event during activation of receptor tyrosine kinases such as the insulin receptor required for normal growth and metabolism. We report that in Drosophila, phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is required to limit PIP3 levels during insulin receptor activation. Depletion of PIP4K increases the levels of PIP3 produced in response to insulin stimulation. We find that PIP4K function at the plasma membrane enhances class I phosphoinositide 3-kinase (PI3K) activity, although the catalytic ability of PIP4K to produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] at the plasma membrane is dispensable for this regulation. Animals lacking PIP4K show enhanced insulin signaling-dependent phenotypes and are resistant to the metabolic consequences of a high-sugar diet, highlighting the importance of PIP4K in normal metabolism and development. Thus, PIP4Ks are key regulators of receptor tyrosine kinase signaling with implications for growth factor-dependent processes including tumor growth, T cell activation, and metabolism.

Keywords: Drosophila; PIP(3); PIP4K; class I PI3K; insulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / enzymology*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Insulin / metabolism*
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Signal Transduction*

Substances

  • Drosophila Proteins
  • Insulin
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Phosphotransferases (Alcohol Group Acceptor)