Practice question

R-spondins 1-4 are cysteine-rich secreted potentiators containing furin and thrombospondin domains amplifying Wnt responses dramatically. They simultaneously bind leucine-rich repeat GPCRs LGR4, LGR5, LGR6 marking stem cells and transmembrane E3 ubiquitin ligases ZNRF3, RNF43 which normally ubiquitinate Frizzled for lysosomal degradation reducing surface receptor availability. R-spondin-LGR complex internalizes and inhibits ZNRF3/RNF43, stabilizing Frizzled receptors increasing membrane availability and amplifying Wnt/beta-catenin signaling several hundred-fold. This sustains intestinal crypt, hair follicle, kidney stem cells. R-spondin alone does not activate pathway, requires Wnt ligand, enhancing sensitivity rather than initiating signaling de novo.