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

Chessa, Tamara A.M.; Jung, Piotr; Anwar, Arqum; Suire, Sabine; Anderson, Karen E.; Barneda, David; Kielkowska, Anna; Sadiq, Barzan A.; Lai, Ieng Wai; Felisbino, Sergio; Turnham, Daniel J.; Pearson, Helen B.; Phillips, Wayne A.; Sasaki, Junko; Sasaki, Takehiko; Oxley, David; Spensberger, Dominik; Segonds-Pichon, Anne; Wilson, Michael; Walker, Simon; Okkenhaug, Hanneke; Cosulich, Sabina; Hawkins, Phillip T.; Stephens, Len R.

Abstract

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression.

• Journal Article Type: Article
• Acceptance Date: Jul 13, 2023
• Online Publication Date: Aug 10, 2023
• Publication Date: Aug 17, 2023
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 23, 2024
• Journal: Molecular Cell
• Print ISSN: 1097-2765
• Electronic ISSN: 1097-4164
• Publisher: Elsevier (Cell Press)
• Peer Reviewed: Peer Reviewed
• Volume: 83
• Issue: 16
• Pages: 2991-3009.e13
• DOI: https://doi.org/10.1016/j.molcel.2023.07.015
• Public URL: https://uwe-repository.worktribe.com/output/13307503