Ring finger protein 181 (RNF181)

Ring finger protein 181 (RNF181) is a RING-type E3 ubiquitin-protein ligase that catalyzes the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins, thereby marking them for proteasomal degradation, altering their cellular location, or modulating their activity. RNF181 is involved in multiple cellular processes: - It interacts with integrin complexes in platelets, linking ubiquitin signaling with platelet function. - In immune cells, RNF181 negatively regulates antigen receptor–mediated activation of NF-κB by promoting ubiquitination and degradation of signaling proteins downstream of the scaffold protein CARD11, thus limiting lymphoma cell proliferation that depends on aberrant NF-κB activation. - RNF181 acts as a tumor suppressor in several cancers (notably gastric, hepatocellular, and oral squamous cell carcinomas), where its loss is linked to increased tumor cell proliferation and survival, mainly through deregulation of cell cycle, MAPK/ERK pathway, and apoptotic machinery. - Conversely, RNF181 can function as an oncoprotein in estrogen receptor–positive breast cancer by stabilizing ERα (estrogen receptor alpha) through K63-linked polyubiquitination, thereby enhancing ERα target gene expression and contributing to tumor progression and endocrine resistance. No specific therapeutics are currently approved or in clinical development that selectively inhibit or modulate RNF181. However, its altered expression and context-dependent roles in cancer highlight both the therapeutic promise and complexity of targeting ubiquitin signaling in disease.

Other names

E3 ubiquitin-protein ligase RNF181HSPC238RING-type E3 ubiquitin transferase RNF181

Not applicable, as there are no known direct-acting drugs. Mechanisms described for RNF181 include: Ubiquitination and modulation of protein stability (e.g., monoubiquitination of the 26S proteasome subunit and K63-linked polyubiquitination of ERα); Negative regulation of NF-κB signaling via CARD11/Bcl10; Influence on cell signaling pathways (MAPK/ERK, cell cycle regulators).