Class IA PI3K p110β subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation

Mol Cell. 2013 Apr 11;50(1):29-42. doi: 10.1016/j.molcel.2013.01.022. Epub 2013 Feb 21.


Autophagy is an evolutionarily conserved membrane trafficking process. Induction of autophagy in response to nutrient limitation or cellular stress occurs by similar mechanisms in organisms from yeast to mammals. Unlike yeast, metazoan cells rely more on growth factor signaling for a wide variety of cellular activities including nutrient uptake. How growth factor availability regulates autophagy is poorly understood. Here we show that, upon growth factor limitation, the p110β catalytic subunit of the class IA phosphoinositide 3-kinases (PI3Ks) dissociates from growth factor receptor complexes and increases its interaction with the small GTPase Rab5. This p110β-Rab5 association maintains Rab5 in its guanosine triphosphate (GTP)-bound state and enhances the Rab5-Vps34 interaction that promotes autophagy. p110β mutants that fail to interact with Rab5 are defective in autophagy promotion. Hence, in mammalian cells, p110β acts as a molecular sensor for growth factor availability and induces autophagy by activating a Rab5-mediated signaling cascade.

Publication types

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

MeSH terms

  • Animals
  • Autophagy*
  • Class I Phosphatidylinositol 3-Kinases / deficiency
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Mice
  • Mice, Knockout
  • Mutation
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Signal Transduction
  • Transfection
  • rab5 GTP-Binding Proteins / metabolism*


  • Intercellular Signaling Peptides and Proteins
  • Guanosine Triphosphate
  • Phosphatidylinositol 3-Kinases
  • 1-phosphatidylinositol 3-kinase p110 subunit, mouse
  • Class I Phosphatidylinositol 3-Kinases
  • Class III Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PIK3CB protein, human
  • Pik3cb protein, mouse
  • rab5 GTP-Binding Proteins