Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
Cell Stem Cell. 2019 Apr 4;24(4):592-607.e7. doi: 10.1016/j.stem.2019.02.002. Epub 2019 Mar 7.
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.
Ral GTPases 是 RAS 效应分子，因此可能成为 RAS 突变型癌症的潜在治疗靶点。然而，人们对它们在干细胞和组织稳态中的作用知之甚少。我们利用果蝇鉴定了 RalA 在肠道干细胞 (ISCs) 和果蝇中肠祖细胞中的表达。RalA 在 Wnt 信号下游的有效再生中，在 ISC 内是必需的。在小鼠肠道中，两种哺乳动物同源物（Rala 或 Ralb）的基因缺失均降低了 ISC 功能和 Lgr5 阳性率，导致对 Wnt 抑制的敏感性增加，并损害损伤后的组织再生。两个基因的缺失导致隐窝迅速死亡。从机制上讲，RALA 和 RALB 对于 Wnt 受体 Frizzled-7 的有效内化是必需的。综上所述，我们鉴定了 RAL GTPases 在促进最佳 Wnt 信号中的保守作用，这决定了 ISC 的数量和再生潜能。
