The transmembrane E3 ubiquitin ligase, Zinc and Ring Finger 3 (ZNRF3), serves as a negative feedback regulator of Wnt signaling. ZNRF3 is associated with the Wnt receptor complex and inhibits Wnt signaling by promoting the turnover of Frizzled and LRP6. Additionally, ZNRF3 functions as a tumor suppressor in the intestinal stem cell compartment by inhibiting the Wnt signaling pathway.