Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom.
Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
Elife. 2021 Jun 7;10:e63807. doi: 10.7554/eLife.63807.
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 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.
RAS 样（RAL）GTPases 在 Wnt 信号依赖性肠道干细胞增殖和再生中发挥作用。RAL 蛋白是否在肠道中作为经典 RAS 效应物发挥作用，以及它们促进肿瘤发生的机制仍不清楚。在这里，我们表明 RAL GTPases 通过诱导 EGFR 内化，对于肠道中 EGFR/MAPK 信号的激活是必需和充分的。敲低肠道干细胞和祖细胞中的 RALB 会导致质膜相关 EGFR 水平升高，MAPK 途径激活减少。重要的是，除了在损伤诱导的肠道再生过程中影响干细胞增殖外，RAL GTPases 的这种作用还会影响肠道和人乳腺上皮中 EGFR 依赖性致瘤性生长。然而，肠内致癌 RAS 的作用与 RAL 功能无关。总的来说，我们的结果揭示了以前未被认识到的细胞和分子环境，RAL GTPases 成为成人组织稳态和恶性转化的重要介质。
