There are four human RSpondin genes in humans whose products are secreted agonists of canonical and non-canonical WNT signaling (Kim et al, 2005; Glinka et al, 2007; reviewed in Kim et al, 2006). RSPO proteins enhance signaling in the presence of WNT ligand and have been shown to bind to the leucine-rich repeat containing G protein coupled receptors (LGR) 4, 5 and 6 (Kim et al, 2005; Binnerts et al, 2007; Carmon et al, 2011; de Lau et al, 2011). RSPO:LGR complexes are postulated to potentiate WNT-dependent signaling in a number of potentially overlapping mechanisms. RSPO proteins enhance WNT-mediated phosphorylation of LRP6 in HEK293 cells (Wei et al, 2007; Binnerts et al, 2007; Carmon et al, 2011). A recent report suggests that this effect may be mediated in part by downregulating the levels of ZNFR3 at the plasma membrane. ZNFR3 is an E3 ubiquitin ligase that has been shown to ubiquitinate FZD and to promote internalization of FZD and LRP6. In the presence of RSPO:LGR, ZNFR3 itself is targeted for internalization, allowing enhanced signaling through the WNT receptor complex (Yao et al, 2012).