E3 ubiquitin-protein ligase RFWD2 (COP1)

E3 ubiquitin-protein ligase RFWD2, commonly known as COP1, is a RING-type E3 ubiquitin ligase that plays a critical role in maintaining cellular proteostasis by targeting various substrates for proteasomal degradation. It functions as a central regulator of the cell cycle, apoptosis, and DNA damage response by mediating the ubiquitination of key proteins such as p53, p27 (Kip1), and members of the ETS transcription factor family [1, 4, 6]. In many human malignancies, including multiple myeloma, breast cancer, and hepatocellular carcinoma, RFWD2 is overexpressed and acts as an oncogene by promoting the degradation of tumor suppressors [3, 6, 20]. Conversely, it can exhibit tumor-suppressive properties in other contexts, such as gastric and colorectal cancers, by targeting oncoproteins like ETV1 [21, 30]. Beyond oncology, RFWD2 is involved in metabolic regulation, where it modulates lipid and glucose metabolism through the degradation of enzymes like ATGL and coactivators like TORC2 [8, 34]. While no FDA-approved drugs specifically target RFWD2, experimental small molecule inhibitors are in preclinical development for metabolic and oncological indications, and RFWD2-NTRK1 fusions are clinically targeted by TRK inhibitors [19, 26, 31].

Other names

Constitutive photomorphogenic 1RING finger and WD repeat domain 2RNF200CFAP78FAP78Constitutive photomorphogenesis protein 1 homolog

Inhibition of E3 ubiquitin ligase activity to stabilize tumor suppressor substrates (e.g., p53, p27) or metabolic regulators (e.g., ATGL); inhibition of RFWD2-NTRK1 fusion protein kinase activity.