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Regulation of EGF-stimulated activation of the PI-3K/AKT pathway by exocyst-mediated exocytosis

Seong J An1,2, Alexander Anneken1, Zhiqun Xi1

  • 1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.

Proceedings of the National Academy of Sciences of the United States of America
|November 23, 2022
PubMed

Insights

The exocyst complex regulates the PI-3K/AKT cell survival pathway in epithelial cells. Exocytosis, mediated by the exocyst, controls PI(3,4,5)P3 levels, impacting AKT activation downstream of EGFR signaling.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Cancer Research

Background:

  • The phosphoinositide-3 kinase (PI-3K)/AKT pathway is crucial for cell survival and is activated by epidermal growth factor receptor (EGFR) signaling.
  • The exocyst complex, a key regulator of exocytosis, has not been previously recognized as a component of this pathway in epithelial cells.

Purpose of the Study:

  • To investigate the role of the exocyst complex in regulating the PI-3K/AKT pathway activation by EGFR.
  • To elucidate the mechanism by which exocytosis influences PI(3,4,5)P3 generation and subsequent AKT activation.

Main Methods:

  • Live-cell imaging to observe PI(3,4,5)P3 dynamics at the plasma membrane.
  • Optogenetic manipulation to promote exocytosis and assess its impact on PI-3K/AKT signaling.
  • Pharmacological inhibition (Endosidin2) and genetic knockdown (siRNA) of exocyst subunits to impair exocytosis.
  • Analysis of AKT activation in response to EGF stimulation and EGFR tyrosine kinase inhibitors.

Main Results:

  • PI(3,4,5)P3 levels fluctuate dynamically at the cell membrane, correlating with exocytic events.
  • Enhanced exocytosis via optogenetics increases PI(3,4,5)P3 production and AKT activation.
  • Inhibition of exocyst function impairs EGF-induced PI(3,4,5)P3 generation and AKT activation.
  • Exocyst inhibition prevents spontaneous AKT reactivation during prolonged EGFR inhibition.

Conclusions:

  • Exocyst-mediated exocytosis is a critical regulator of PI-3K/AKT pathway activation in epithelial cells.
  • The exocyst complex controls PI(3,4,5)P3 levels at the plasma membrane, thereby modulating EGFR signaling.
  • Targeting the exocyst complex offers a potential strategy to modulate PI-3K/AKT pathway activity in diseases driven by EGFR signaling.
Keywords:
biochemistrybiological sciencescell biology

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