RNF43 and related protein ZNRF3 are E3 ubiquitin ligases that negatively regulate WNT signaling by downregulating FZD receptors at the cell surface (Mukai et al, 2010; Hao et al, 2012). Frameshift loss-of-function mutations in RNF43 that enhance WNT signaling have been identified in pancreatic and colorectal cancers; the proliferation of these cells is dependent on the presence of secreted WNT, as their growth is abrogated by treatment of cells with the Porcupine inhibitor LGK974 (Koo et al, 2012; Jiang et al, 2013).
