Ring finger and WD repeat domain 2 (RFWD2)

Ring finger and WD repeat domain 2 (RFWD2), also known as COP1, is a RING-type E3 ubiquitin ligase that plays a critical role in regulating protein stability through the ubiquitin-proteasome system [UniProt: Q8NHY2]. It acts as a central scaffold within the Cullin 4-based E3 ubiquitin ligase complex, targeting various substrates for degradation, including the tumor suppressor p53 and the transcription factors c-Jun and ETV1 [PubMed: 15103331, 21135137]. In many human cancers, RFWD2 is frequently overexpressed, where it functions as an oncogene by promoting the degradation of tumor suppressors or stabilizing oncoproteins [PubMed: 24633280]. Beyond its role in oncology, RFWD2 is involved in metabolic regulation, specifically influencing lipid metabolism and glucose homeostasis [PubMed: 22351778]. As a therapeutic target, efforts are focused on developing small molecule inhibitors or PROTACs to disrupt its interaction with key substrates, particularly in p53-wildtype or ETV1-driven tumors [PubMed: 30104363]. However, the broad substrate specificity of RFWD2 presents challenges in achieving therapeutic selectivity and avoiding systemic toxicity. Its role in the DNA damage response further complicates its inhibition, as it may affect genomic stability [PubMed: 17332767]. Overall, RFWD2 represents a promising but complex target in precision medicine, requiring careful consideration of the cellular context and substrate profile.

Other names

COP1Constitutive photomorphogenesis protein 1 homologRNF200RING finger protein 200

RFWD2 functions as an E3 ubiquitin ligase that facilitates the transfer of ubiquitin from an E2 enzyme to specific substrate proteins, marking them for 26S proteasomal degradation [UniProt: Q8NHY2].