Among R-Spondins (RSPO) ligands family, RSPO2 binding to Lgr5 regulates receptor turnover through stabilization of tumor suppressors ZNFR3 and RNF43 membrane E3 ligases, that mediate ubiquitination and consequent degradation of LRP6/5 receptors (Hao et al., 2016). Here, RSPO2 is linked to neoplasm.