E3 ubiquitin-protein ligase ZNRF2 (ZNRF2)

E3 ubiquitin-protein ligase ZNRF2 (ZNRF2) is an enzyme belonging to the RING finger protein family, characterized by a unique zinc finger and RING finger motif. ZNRF2 acts as an E3 ubiquitin ligase, mediating the transfer of ubiquitin to target proteins, which regulates their degradation, trafficking, or signaling roles in the cell. ZNRF2 is membrane-associated but can translocate to the cytosol upon phosphorylation; it is expressed throughout human tissues with higher levels in specific tissues and tumors, and is particularly abundant in the nervous system. In neurons, it maintains synaptic transmission and plasticity, partly via the ubiquitination of the Na^+/K^+ ATPase α1 subunit. ZNRF2 also regulates mTORC1 activation by amino acids, acting upstream of the V-ATPase and Rag GTPases, and can influence cellular processes such as cell growth, proliferation, and survival. Dysregulated ZNRF2 expression is implicated in oncogenesis, notably in non-small cell lung cancer and hepatocellular carcinoma, where it promotes tumor growth and poor prognosis. However, no direct inhibitors or drugs currently target ZNRF2 in clinical use. Given its critical roles in cellular homeostasis and disease, ZNRF2 is considered a promising but challenging therapeutic target.

Other names

Zinc and ring finger 2RING finger protein 202RING-type E3 ubiquitin transferase ZNRF2RNF202Protein Ells2Zinc/RING finger protein 2E3 ubiquitin protein ligaseZinc finger/RING finger 2

Targeted drugs would likely act by inhibiting E3 ubiquitin ligase activity, blocking protein-protein interaction with substrates such as Na^+/K^+ ATPase or mTORC1 pathway members, or modulating its phosphorylation and subcellular localization