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RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes.
Johansson, Joel; Naszai, Mate; Hodder, Michael C; Pickering, Karen A; Miller, Bryan W; Ridgway, Rachel A; Yu, Yachuan; Peschard, Pascal; Brachmann, Saskia; Campbell, Andrew D; Cordero, Julia B; Sansom, Owen J.
Afiliação
  • Johansson J; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Naszai M; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
  • Hodder MC; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Pickering KA; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Miller BW; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Ridgway RA; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Yu Y; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
  • Peschard P; McGill University, Montréal, Quebec, Canada.
  • Brachmann S; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Campbell AD; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Cordero JB; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: julia.cordero@glasgow.ac.uk.
  • Sansom OJ; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: o.sansom@beatson.gla.ac.uk.
Cell Stem Cell ; 24(4): 592-607.e7, 2019 04 04.
Article em En | MEDLINE | ID: mdl-30853556
Ral GTPases are RAS effector molecules and by implication a potential therapeutic target for RAS mutant cancer. However, very little is known about their roles in stem cells and tissue homeostasis. Using Drosophila, we identified expression of RalA in intestinal stem cells (ISCs) and progenitor cells of the fly midgut. RalA was required within ISCs for efficient regeneration downstream of Wnt signaling. Within the murine intestine, genetic deletion of either mammalian ortholog, Rala or Ralb, reduced ISC function and Lgr5 positivity, drove hypersensitivity to Wnt inhibition, and impaired tissue regeneration following damage. Ablation of both genes resulted in rapid crypt death. Mechanistically, RALA and RALB were required for efficient internalization of the Wnt receptor Frizzled-7. Together, we identify a conserved role for RAL GTPases in the promotion of optimal Wnt signaling, which defines ISC number and regenerative potential.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco / Proteínas Monoméricas de Ligação ao GTP / Proteínas de Drosophila / Proteínas Wnt / Via de Sinalização Wnt Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco / Proteínas Monoméricas de Ligação ao GTP / Proteínas de Drosophila / Proteínas Wnt / Via de Sinalização Wnt Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article