R-spondins (RSPO) are secreted Wnt agonists and generally neutralizes RNF43/ZNRF3 by interacting with leucine-rich repeat containing G protein-coupled receptors (LGRs), enhancing Wnt signaling under low-dose Wnt, which is attenuated by tumor-suppressive E3 ligases NEDD4 and its homologue NEDD4L through targeting LGR5 for both lysosomal and proteasomal degradation [86]. Here, NEDD4 is linked to neoplasm.