RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes.

Autor: 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.
Jazyk: angličtina
Zdroj: Cell stem cell [Cell Stem Cell] 2019 Apr 04; Vol. 24 (4), pp. 592-607.e7. Date of Electronic Publication: 2019 Mar 07.
DOI: 10.1016/j.stem.2019.02.002
Abstrakt: 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.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE