Quantitative Lipid Imaging Reveals a New Signaling Function of Phosphatidylinositol-3,4-Bisphophate: Isoform- and Site-Specific Activation of Akt

Mol Cell. 2018 Sep 20;71(6):1092-1104.e5. doi: 10.1016/j.molcel.2018.07.035. Epub 2018 Aug 30.


Activation of class I phosphatidylinositol 3-kinase (PI3K) leads to formation of phosphatidylinositol-3,4,5-trisphophate (PIP3) and phosphatidylinositol-3,4-bisphophate (PI34P2), which spatiotemporally coordinate and regulate a myriad of cellular processes. By simultaneous quantitative imaging of PIP3 and PI34P2 in live cells, we here show that they have a distinctively different spatiotemporal distribution and history in response to growth factor stimulation, which allows them to selectively induce the membrane recruitment and activation of Akt isoforms. PI34P2 selectively activates Akt2 at both the plasma membrane and early endosomes, whereas PIP3 selectively stimulates Akt1 and Akt3 exclusively at the plasma membrane. These spatiotemporally distinct activation patterns of Akt isoforms provide a mechanism for their differential regulation of downstream signaling molecules. Collectively, our studies show that different spatiotemporal dynamics of PIP3 and PI34P2 and their ability to selectively activate key signaling proteins allow them to mediate class I PI3K signaling pathways in a spatiotemporally specific manner.

Keywords: Akt activation mechanism; PI34P2 quantification; PI3K signaling; PIP3 quantification.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane
  • Humans
  • Inositol Phosphates
  • Mice
  • Optical Imaging / methods*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphatidylinositol Phosphates / physiology*
  • Phosphatidylinositols
  • Protein Isoforms
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Single Molecule Imaging / methods*


  • Inositol Phosphates
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Protein Isoforms
  • phosphatidylinositol 3,4,5-triphosphate
  • phosphatidylinositol 3,4-diphosphate
  • Phosphatidylinositol 3-Kinases
  • AKT2 protein, human
  • AKT3 protein, human
  • Proto-Oncogene Proteins c-akt