A high-avidity biosensor reveals plasma membrane PI(3,4)P2 is predominantly a class I PI3K signaling product

J Cell Biol. 2019 Mar 4;218(3):1066-1079. doi: 10.1083/jcb.201809026. Epub 2018 Dec 27.

Abstract

Class I phosphoinositide 3-OH kinase (PI3K) signaling is central to animal growth and metabolism, and pathological disruption of this pathway affects cancer and diabetes. However, the specific spatial/temporal dynamics and signaling roles of its minor lipid messenger, phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2), are not well understood. This owes principally to a lack of tools to study this scarce lipid. Here we developed a high-sensitivity genetically encoded biosensor for PI(3,4)P2, demonstrating high selectivity and specificity of the sensor for the lipid. We show that despite clear evidence for class II PI3K in PI(3,4)P2-driven function, the overwhelming majority of the lipid accumulates through degradation of class I PI3K-produced PIP3 However, we show that PI(3,4)P2 is also subject to hydrolysis by the tumor suppressor lipid phosphatase PTEN. Collectively, our results show that PI(3,4)P2 is potentially an important driver of class I PI3K-driven signaling and provides powerful new tools to begin to resolve the biological functions of this lipid downstream of class I and II PI3K.

Publication types

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

MeSH terms

  • Animals
  • Biosensing Techniques*
  • COS Cells
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • HeLa Cells
  • Humans
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol Phosphates / genetics
  • Phosphatidylinositol Phosphates / metabolism*
  • Signal Transduction*

Substances

  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4-diphosphate
  • PTEN Phosphohydrolase
  • PTEN protein, human