R-spondins are secreted Wnt signalling agonists, which regulate embryonic patterning and stem cell proliferation, but whose mechanism of action is poorly understood. Here we show that R-spondins bind to the orphan G-protein-coupled receptors LGR4 and LGR5 by their Furin domains. Gain- and loss-of-function experiments in mammalian cells and Xenopus embryos indicate that LGR4 and LGR5 promote R-spondin-mediated Wnt/β-catenin and Wnt/PCP signalling. R-spondin-triggered β-catenin signalling requires Clathrin, while Wnt3a-mediated β-catenin signalling requires Caveolin-mediated endocytosis, suggesting that internalization has a mechanistic role in R-spondin signalling.
PubMed ID: 21909076
PMC ID: PMC3185347
Article link: EMBO Rep.
Genes referenced: furin lgr4 lgr5 wnt3a
Morpholinos referenced: lgr4 MO1 lgr4 MO2 lgr4 MO3 lgr5 MO1 lgr5 MO2 lgr5 MO3