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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
Summary
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.
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