RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis

Nászai, M. et al. (2021) RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis. eLife, 10, e63807. (doi: 10.7554/eLife.63807) (PMID:34096503) (PMCID:PMC8216719)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Roman Fernandez, Mr Alvaro and Sansom, Professor Owen and Campbell, Dr Andrew and Yu, Dr Yachuan and Norman, Professor James and Cordero, Dr Julia and Bryant, Dr David and Sandilands, Dr Emma and Naszai, Mr Mate and Bellec, Miss Karen
Authors: Nászai, M., Bellec, K., Yu, Y., Román-Fernández, Á., Sandilands, E., Johansson, J., Campbell, A. D., Norman, J. C., Sansom, O. J., Bryant, D. M., and Cordero, J. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
Published Online:07 June 2021
Copyright Holders:Copyright © 2021 Nászai et al.
First Published:First published in eLife 10: e63807
Publisher Policy:Reproduced under a Creative Commons License
Data DOI:10.5525/gla.researchdata.1142

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190860Regulation of stem cell function during tissue homeostasis and transformationJulia CorderoWellcome Trust (WELLCOTR)104103/Z/14/ZInstitute of Cancer Sciences
190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076Institute of Cancer Sciences