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

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MetadadosDescriçãoIdioma
Autor(es): dc.contributorBabraham Institute-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorCardiff University-
Autor(es): dc.contributorUniversity of Melbourne-
Autor(es): dc.contributorTokyo Medical and Dental University-
Autor(es): dc.contributorAstraZeneca-
Autor(es): dc.creatorChessa, Tamara A.M.-
Autor(es): dc.creatorJung, Piotr-
Autor(es): dc.creatorAnwar, Arqum-
Autor(es): dc.creatorSuire, Sabine-
Autor(es): dc.creatorAnderson, Karen E.-
Autor(es): dc.creatorBarneda, David-
Autor(es): dc.creatorKielkowska, Anna-
Autor(es): dc.creatorSadiq, Barzan A.-
Autor(es): dc.creatorLai, Ieng Wai-
Autor(es): dc.creatorFelisbino, Sergio-
Autor(es): dc.creatorTurnham, Daniel J.-
Autor(es): dc.creatorPearson, Helen B.-
Autor(es): dc.creatorPhillips, Wayne A.-
Autor(es): dc.creatorSasaki, Junko-
Autor(es): dc.creatorSasaki, Takehiko-
Autor(es): dc.creatorOxley, David-
Autor(es): dc.creatorSpensberger, Dominik-
Autor(es): dc.creatorSegonds-Pichon, Anne-
Autor(es): dc.creatorWilson, Michael-
Autor(es): dc.creatorWalker, Simon-
Autor(es): dc.creatorOkkenhaug, Hanneke-
Autor(es): dc.creatorCosulich, Sabina-
Autor(es): dc.creatorHawkins, Phillip T.-
Autor(es): dc.creatorStephens, Len R.-
Data de aceite: dc.date.accessioned2025-08-21T21:12:43Z-
Data de disponibilização: dc.date.available2025-08-21T21:12:43Z-
Data de envio: dc.date.issued2025-04-29-
Data de envio: dc.date.issued2023-08-17-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.molcel.2023.07.015-
Fonte completa do material: dc.identifierhttps://hdl.handle.net/11449/305522-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/305522-
Descrição: dc.descriptionThe 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.-
Descrição: dc.descriptionCancer Research UK-
Descrição: dc.descriptionBabraham Institute-
Descrição: dc.descriptionBiotechnology and Biological Sciences Research Council-
Descrição: dc.descriptionMedical Research Council-
Descrição: dc.descriptionSignalling Programme Babraham Institute-
Descrição: dc.descriptionDepartment of Structural and Functional Biology São Paulo State University, SP-
Descrição: dc.descriptionEuropean Cancer Stem Cell Research Institute Cardiff University-
Descrição: dc.descriptionPeter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology University of Melbourne-
Descrição: dc.descriptionDepartment of Biochemical Pathophysiology Medical Research Institute Tokyo Medical and Dental University-
Descrição: dc.descriptionMass Spectrometry Facility Babraham Institute-
Descrição: dc.descriptionGene Targeting Facility Babraham Institute-
Descrição: dc.descriptionBioinformatics Babraham Institute-
Descrição: dc.descriptionImaging Facility Babraham Institute-
Descrição: dc.descriptionProjects Group Oncology R&D AstraZeneca-
Descrição: dc.descriptionDepartment of Structural and Functional Biology São Paulo State University, SP-
Descrição: dc.descriptionBiotechnology and Biological Sciences Research Council: BB/P013384/1-
Descrição: dc.descriptionBiotechnology and Biological Sciences Research Council: BB/P020240/1-
Descrição: dc.descriptionMedical Research Council: MR/R000409/1-
Formato: dc.format2991-3009.e13-
Idioma: dc.languageen-
Relação: dc.relationMolecular Cell-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectIRS1-
Palavras-chave: dc.subjectPI3K-
Palavras-chave: dc.subjectPLEKHS1-
Palavras-chave: dc.subjectprostate-
Palavras-chave: dc.subjectPTEN-
Palavras-chave: dc.subjectSrc-family kinase-
Título: dc.titlePLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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