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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.
Afiliación
  • 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.
Mol Cell ; 83(16): 2991-3009.e13, 2023 08 17.
Article en En | MEDLINE | ID: mdl-37567175
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Fosfohidrolasa PTEN Límite: Animals / Humans / Male Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Fosfohidrolasa PTEN Límite: Animals / Humans / Male Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos