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GqPCR-stimulated dephosphorylation of AKT is induced by an IGBP1-mediated PP2A switch

Guy Nadel1, Zhong Yao1, Ehud Wainstein1

  • 1Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.

Cell Communication and Signaling : CCS
|January 9, 2022
PubMed
Abstract

Insights

G protein-coupled receptors (GPCRs) trigger apoptosis by inactivating the AKT pathway. This involves a novel "PP2A switch" mechanism where the phosphatase PP2A shifts from PI3K to AKT, repressing the PI3K/AKT signaling pathway.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Signal Transduction

Background:

  • G protein-coupled receptors (GPCRs) typically activate cellular processes.
  • Previously observed: GPCRs can inactivate the AKT pathway, leading to apoptosis.
  • This AKT inactivation is crucial for GPCR physiological functions.

Purpose of the Study:

  • To elucidate the mechanism behind GPCR-induced AKT inactivation.
  • To identify the key regulators involved in this signaling pathway.

Main Methods:

  • Kinase activity assays for PI3K.
  • Western blotting with phospho-specific antibodies.
  • Co-immunoprecipitation and proximity ligation assays.
  • Apoptosis detection via TUNEL assay and PARP1 cleavage.

Main Results:

  • Identified Protein Phosphatase 2A (PP2A) and its subunit IGBP1 as key regulators.
  • Discovered a mechanism where PP2A shifts from PI3K to AKT upon GPCR activation (the "PP2A switch").
  • This switch leads to PI3K inhibition and AKT dephosphorylation/inactivation.

Conclusions:

  • The "PP2A switch" is a novel mechanism for GPCR-mediated repression of the PI3K/AKT pathway.
  • This process involves stimulated dephosphorylation of PI3K and AKT.
  • Provides new insights into GPCR signaling and its role in apoptosis.
Keywords:
AKTIGBP1PI3KPKCPP2A

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