RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes

Abstract

Summary 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 mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

“…RAL small GTPases are best recognised for their role as effectors of Ras signalling, which has attracted basic and translational research into their potential in cancer development and progression (Moghadam et al, 2017). We recently identified a novel role of RAL GTPases in the regulation of Wnt signalling activity in ISCs through the regulation of Wnt receptor trafficking into intracellular compartments (Johansson et al, 2019). The relevance of RAL GTPases in intestinal tumorigenesis remained unaddressed as their function in the intestine became redundant upon loss of Adenomatous polyposis coli, a key driver of colorectal cancer (Johansson et al, 2019).…”

“…We recently identified a novel role of RAL GTPases in the regulation of Wnt signalling activity in ISCs through the regulation of Wnt receptor trafficking into intracellular compartments (Johansson et al, 2019). The relevance of RAL GTPases in intestinal tumorigenesis remained unaddressed as their function in the intestine became redundant upon loss of Adenomatous polyposis coli, a key driver of colorectal cancer (Johansson et al, 2019). Furthermore, whether RAL proteins (RALs) can impact intestinal biology 6 beyond Wnt signalling and whether this occurs through their classical role as Ras effectors is unclear.…”

High Canonical Wnt/β-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage

“…A wealth of studies has proved that the Wnt signaling pathway is essential for self-renewal and regeneration activities upon injury of the ISCs [35][36][37], which supports the hypothesis that instructed enhancement of Wnt signaling would benefit intestinal regeneration after irradiation. For instance, it was shown that activation of Wnt signaling resulted in less apoptosis and enhanced proliferation after IR in the gastrointestinal system [38,39].…”

RALying Regeneration through Wnt Internalization in Stem Cells

“…In this issue of Cell Stem Cell, Johansson et al (2019) find evolutionarily conserved regulation of Wnt signaling through Ral GTPases. These GTPases promote internalization of Wnt receptor complexes and play a critical role in intestinal stem cell function in flies and mice.…”

“…Understanding fundamental mechanisms of Wnt signaling activity is thus expected to provide insight into possible intervention strategies for a range of diseases, including intestinal cancers and inflammatory diseases. In this issue of Cell Stem Cell, Johansson et al (2019) uncover a conserved role for Ras-like (RAL) GTPases as key regulators of Wnt signaling in intestinal homeostasis and regeneration in both flies and mice. RAL GTPases are multifunctional RAS effectors implicated in diverse cellular pro-cesses, including actin dynamics, exocyst function, and membrane trafficking, and they have been extensively studied in the context of human cancers (Yan and Theodorescu, 2018).…”