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 influencing stem cell proliferation during damage-induced intestinal regeneration, this role of RAL GTPases impacts on EGFR-dependent tumourigenic 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.
Highlights
The precise spatial and temporal regulation of signalling pathway activity is essential for organ development and adult tissue homeostasis
While RAL proteins (RALs) inhibition is an efficient means of attenuating intestinal hyperplasia caused by constitutively active forms of EGFR, the effect of oncogenic Ras in the intestine is insensitive to attenuation of RAL function
The impact of this process in adult stem cells and tissue homeostasis is only recently becoming evident from reports on the effect of endocytosis and autophagy on intestinal stem cells (ISCs) proliferation through modulation of Wnt/b-catenin and EGFR/MAPK activity, respectively (Johansson et al, 2019; Zhang et al, 2019)
Summary
The precise spatial and temporal regulation of signalling pathway activity is essential for organ development and adult tissue homeostasis. The latter is important in stem cell maintained self-renewing epithelia, such as that of the gastrointestinal tract (Richardson et al, 2014), where cell loss needs to be counteracted by stem cell proliferation and differentiation while limiting the potential for unwanted overgrowth (Radtke and Clevers, 2005). Regulation of intestinal homeostasis involves the coordinated action of multiple evolutionarily conserved signalling pathways, which relay environmental and niche-derived signals to stem cells to determine their activity (Gehart and Clevers, 2019; Naszai et al, 2015; Scoville et al, 2008).
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