R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and β-catenin signaling. Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate β-catenin-dependent gene expression. R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. R-spondin1 is essential in sex determination, skin differentiation and malignancy. The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. The gene encoding R-spondin 4 ( RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. R-spondin3 is required for mouse placental development. Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. R-Spondin family members regulate the Wnt pathway by a common mechanism. Mitogenic influence of human R-spondin1 on the intestinal epithelium. R-Spondin2 is a secreted activator of Wnt/β-catenin signaling and is required for Xenopus myogenesis. Planar cell polarity signaling: from fly development to human disease. Wnt/β-catenin signaling: components, mechanisms, and diseases. Wnt/β-catenin signaling in development and disease. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.Ĭlevers, H. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Inhibition of ZNRF3 enhances Wnt/β-catenin signalling and disrupts Wnt/planar cell polarity signalling in vivo. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action remains unclear. R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |