RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis
- University of Oxford, United Kingdom
- University of Glasgow, United Kingdom
- CRUK Beatson Institute, United Kingdom
- Beatson Institute, United Kingdom
Abstract
RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumourigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine, via induction of EGFR internalisation. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation during damage-induced intestinal regeneration, this role of RAL GTPases impacts on EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. However, the effect of oncogenic RAS in the intestine is independent from RAL function. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of adult tissue homeostasis and malignant transformation.
Data availability
All data underlying the findings of this study are included in the manuscript and supporting file. Source data files have been provided for all figures containing numeric data. The entire raw data set corresponding to the work in this paper will be publicly available at the time of publication from our institutional repository http://dx.doi.org/10.5525/gla.researchdata.1142. RNA sequencing data has been deposited in GEO (accession GSE162421) and can be accessed through (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162421). Custom scripts used for quantification are available at Github: https://github.com/emltwc/TracheaProject/blob/master/Blind_scoring.ijm; https://github.com/emltwc/2018-Cell-Stem-Cell and https://github.com/emltwc/EGFRProject .
Article and author information
Author details
Funding
Wellcome Trust (104103/Z/14/Z)
- Julia B Cordero
Cancer Research UK (A17196)
- Yachuan Yu
Cancer Research UK (A18277,C596/A18076)
- Jim C Norman
Cancer Research UK (A21139)
- Joel Johansson
- Andrew D Campbell
- Owen J Sansom
Cancer Research UK (A17196)
- Alvaro Román-Fernández
- Emma Sandilands
- David M Bryant
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hugo J Bellen, Baylor College of Medicine, United States
Ethics
Animal experimentation: All animal work has been approved by a University of Glasgow internal ethics committee and performed in accordance with institutional guidelines under personal and project licenses granted by the UK Home Office (PPL PCD3046BA).
Version history
- Received: October 7, 2020
- Accepted: June 3, 2021
- Accepted Manuscript published: June 7, 2021 (version 1)
- Version of Record published: June 21, 2021 (version 2)
Copyright
© 2021, Nászai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis
eLife 10:e63807.
https://doi.org/10.7554/eLife.63807
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