Dataset Information

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

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 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 signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. 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-signalling and supports tumour progression.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Prostate Gland

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: David Oxley

LAB HEAD: David Oxley

PROVIDER: PXD043239 | Pride | 2023-08-23

REPOSITORIES: Pride

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

Chessa Tamara A M TAM Jung Piotr P Anwar Arqum A Suire Sabine S Anderson Karen E KE Barneda David D Kielkowska Anna A Sadiq Barzan A BA Lai Ieng Wai IW Felisbino Sergio S Turnham Daniel J DJ Pearson Helen B HB Phillips Wayne A WA Sasaki Junko J Sasaki Takehiko T Oxley David D Spensberger Dominik D Segonds-Pichon Anne A Wilson Michael M Walker Simon S Okkenhaug Hanneke H Cosulich Sabina S Hawkins Phillip T PT Stephens Len R LR

Molecular cell 20230810 16

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 remo ...[more]

PMID: 37567175

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Project description:Phosphatase activities on PI(3,4,5)P3 and PI(3,4)P2 This model describes the action of various phosphatases on PI(3,4,5)P3 and PI(3,4)P2, in response to a stimulation by EGF. It contains boolean switches to simulate knock-down and knock-out of phosphatases as well as inhibition of PI3 kinase. This model is described in the article: PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K Mouhannad Malek, Anna Kielkowska, Tamara Chessa, Karen E. Anderson, David Barneda, P?nar Pir, Hiroki Nakanishi, Satoshi Eguchi, Atsushi Koizumi, Junko Sasaki, Véronique Juvin, Vladimir Y. Kiselev, Izabella Niewczas, Alexander Gray, Alexandre Valayer, Dominik Spensberger, Marine Imbert, Sergio Felisbino, Tomonori Habuchi, Soren Beinke, Sabina Cosulich, Nicolas Le Novère, Takehiko Sasaki, Jonathan Clark, Phillip T. Hawkins and Len R. Stephens Molecular Cell Abstract: The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P2 in the phenotype caused by loss-of-function mutations or deletions in PTEN. This model is hosted on BioModels Database and identified by: MODEL1704190000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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