Endomembrane PtdIns(3,4,5)P3 activates the PI3K-Akt pathway

Nirmal Jethwa, Gary H C Chung, Marta G Lete, Alicia Alonso, Richard D Byrne, Véronique Calleja, Banafshé Larijani

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

PKB/Akt activation is a common step in tumour growth, proliferation and survival. Akt activation is understood to occur at the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] following phosphoinositide 3-kinase (PI3K) activation. The metabolism and turnover of phosphoinositides is complex--they act as signalling molecules as well as structural components of biological membranes. The localisation and significance of internal pools of PtdIns(3,4,5)P3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P3, we show that PtdIns(3,4,5)P3 is enriched in the nuclear envelope and early endosomes. By exploiting an inducible dimerisation device to recruit Akt to these compartments, we demonstrate that Akt can be locally activated in a PtdIns(3,4,5)P3-dependent manner and has the potential to phosphorylate compartmentally localised downstream substrates. This could be an important mechanism to regulate Akt isoform substrate specificity or influence the timing and duration of PI3K pathway signalling. Defects in phosphoinositide metabolism and localisation are known to contribute to cancer, suggesting that interactions at subcellular compartments might be worthwhile targets for therapeutic intervention.

Original languageEnglish
Pages (from-to)3456-3465
Number of pages10
JournalJournal of Cell Science
Volume128
Issue number18
DOIs
Publication statusPublished - 15 Sep 2015

Keywords

  • Cell Membrane/metabolism
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Phosphatidylinositol 3-Kinases/metabolism
  • Phosphatidylinositol Phosphates/metabolism
  • Phosphorylation
  • Protein Transport
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction
  • Substrate Specificity
  • Transfection

Fingerprint Dive into the research topics of 'Endomembrane PtdIns(3,4,5)P3 activates the PI3K-Akt pathway'. Together they form a unique fingerprint.

Cite this