Zinc and ring finger protein 3 (ZNRF3)

Zinc and ring finger protein 3 (ZNRF3) is a transmembrane E3 ubiquitin-protein ligase that serves as a critical negative regulator of the Wnt signaling pathway [1, 2]. It functions by binding to and ubiquitinating Wnt receptor complex components, specifically Frizzled (FZD) and LRP6, leading to their internalization and lysosomal degradation [1, 3]. This process effectively dampens both canonical and non-canonical Wnt signaling, making ZNRF3 a key tumor suppressor in various tissues, particularly the intestine and adrenal gland [2, 3]. In many cancers, ZNRF3 is inactivated through mutations or deletions, leading to hypersensitivity to Wnt ligands and uncontrolled cell proliferation [3, 4]. Conversely, therapeutic strategies such as R-spondin mimetics (e.g., SZN-043) aim to inhibit ZNRF3 to promote tissue regeneration in conditions like alcoholic hepatitis or bone loss [5, 6]. However, the therapeutic modulation of ZNRF3 requires precise control to avoid the risks of oncogenesis associated with constitutive Wnt pathway activation [4, 5]. ZNRF3 also plays essential roles in embryonic development, including limb specification, sex determination, and brain development [1, 2]. Its activity is naturally modulated by R-spondin proteins, which sequester ZNRF3 from the cell surface to enhance Wnt signaling [1, 3].

Other names

RNF203KIAA1133BK747E2.3E3 ubiquitin-protein ligase ZNRF3RING finger protein 203

Inhibition of E3 ligase activity and induction of membrane clearance to stabilize Frizzled receptors and activate Wnt signaling.