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

Chessa, TAM; Jung, P; Anwar, A; Suire, S; Anderson, KE; Barneda, D; Kielkowska, A; Sadiq, BA; Lai, IW; Felisbino, S; Turnham, DJ; Pearson, HB; Phillips, WA; Sasaki, J; Sasaki, T; Oxley, D; Spensberger, D; Segonds-Pichon, A; Wilson, M; Walker, S; Okkenhaug, H; Cosulich, S; Hawkins, PT; Stephens, LR

Author(s): Chessa, TAM; Jung, P; Anwar, A; Suire, S; Anderson, KE; Barneda, D; Kielkowska, A; Sadiq, BA; Lai, IW; Felisbino, S; Turnham, DJ; Pearson, HB; Phillips, WA; Sasaki, J; Sasaki, T; Oxley, D; Spensberger, D; Segonds-Pichon, A; Wilson, M; Walker, S; Okkenhaug, H; Cosulich, S; Hawkins, PT; Stephens, LR;
Details: Publication Year 2023-08-17,Volume 83,Issue #16,Page 2991-3009.e13
Journal Title: Molecular Cell
Publication Type: Research article
Abstract: The PIP(3)/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP(3)/PI(3,4)P(2) 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 PIP(3)/PI(3,4)P(2)-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP(3), 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 Y(258)XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y(419) 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 PIP(3) signaling, and supports tumor progression.
Publisher: Cell Press
Keywords: Animals; Humans; Male; Mice; Homeostasis; Phosphatidylinositol 3-Kinases/genetics/metabolism; Prostate/pathology; *Prostatic Neoplasms/genetics/pathology; Proto-Oncogene Proteins c-akt/genetics/metabolism; *PTEN Phosphohydrolase/genetics/metabolism; Irs1; Pi3k; Plekhs1; Pten; Src-family kinase; prostate
Department(s): Laboratory Research
PubMed ID: 37567175
Publisher's Version: https://doi.org/10.1016/j.molcel.2023.07.015
Open Access at Publisher's Site: https://doi.org/10.1016/j.molcel.2023.07.015
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-25 06:30:01

Last Modified: 2023-10-25 06:33:22