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

Autor: Chessa TAM; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: tamara.chessa@babraham.ac.uk., Jung P; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Anwar A; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Suire S; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Anderson KE; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Barneda D; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Kielkowska A; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Sadiq BA; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Lai IW; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Felisbino S; Department of Structural and Functional Biology, São Paulo State University, Botucatu, SP CEP: 18618-689, Brazil., Turnham DJ; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK., Pearson HB; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK., Phillips WA; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Sasaki J; Department of Biochemical Pathophysiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan., Sasaki T; Department of Biochemical Pathophysiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan., Oxley D; Mass Spectrometry Facility, Babraham Institute, Cambridge CB22 3AT, UK., Spensberger D; Gene Targeting Facility, Babraham Institute, Cambridge CB22 3AT, UK., Segonds-Pichon A; Bioinformatics, Babraham Institute, Cambridge CB22 3AT, UK., Wilson M; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Walker S; Imaging Facility, Babraham Institute, Cambridge CB22 3AT, UK., Okkenhaug H; Imaging Facility, Babraham Institute, Cambridge CB22 3AT, UK., Cosulich S; Projects Group, Oncology R&D, AstraZeneca, Cambridge, UK., Hawkins PT; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK., Stephens LR; Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: len.stephens@babraham.ac.uk.
Jazyk: angličtina
Zdroj: Molecular cell [Mol Cell] 2023 Aug 17; Vol. 83 (16), pp. 2991-3009.e13. Date of Electronic Publication: 2023 Aug 10.
DOI: 10.1016/j.molcel.2023.07.015
Abstrakt: 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.
Competing Interests: Declaration of interests S.C. is an employee of AZ. We, the authors, have a patent related to this work (patent application number 2304156.9, granted by United Kingdom Patent Office, covering “modulating PLEKHS1 activity in a cell”).
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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