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PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate

Tamara A M Chessa1, Piotr Jung1, Arqum Anwar1

  • 1Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK.

Molecular Cell
|August 11, 2023
PubMed

Insights

In PTEN-null prostate cancer, PLEKHS1 adaptor protein drives overactive PIP3/PI3K signaling by evading feedback and promoting AKT phosphorylation, supporting tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • The Phosphoinositide 3-kinase (PI3K) network regulates metabolism and is often hyperactivated in cancer, frequently due to loss of the PTEN phosphatase.
  • Understanding the drivers of the PI3K network in normal tissues and its adaptation to overactivation is crucial for cancer research.

Purpose of the Study:

  • To investigate the signaling network driving PI3K activity in healthy and PTEN-null mouse prostate.
  • To identify key molecular players and mechanisms responsible for sustained PI3K pathway activation in the absence of PTEN.

Main Methods:

  • Analysis of PI3K network signaling in mouse prostate models.
  • Identification and characterization of protein-protein interactions and post-translational modifications.
  • Correlation analysis of molecular markers with PI3K pathway activity in human prostate cancer samples.

Main Results:

  • In healthy mouse prostate, PI3K activity is regulated by RTK/IRS signaling and feedback inhibition.
  • In PTEN-null prostate, the adaptor protein PLEKHS1 becomes a dominant activator of the PI3K network.
  • PLEKHS1 sustains PIP3 levels and AKT phosphorylation by evading feedback and undergoing enhanced phosphorylation at YXXM motif, driven by PI3K and Src-family kinases.

Conclusions:

  • PLEKHS1 acts as a critical mediator of PI3K pathway activation in PTEN-deficient prostate cancer.
  • Receptor-independent, Src-dependent phosphorylation of PLEKHS1 creates a positive feedback loop that drives tumor progression.
  • PLEKHS1 and Src activation are potential biomarkers and therapeutic targets in human prostate cancers with PI3K pathway activation.
Keywords:
IRS1PI3KPLEKHS1PTENSrc-family kinaseprostate

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