E3 ubiquitin-protein ligase ARK2C (ARK2C)

E3 ubiquitin-protein ligase ARK2C (ARK2C, also known as RNF165) is a RING finger E3 ligase belonging to the Arkadia family, with a key role in *ubiquitin-dependent protein degradation pathways*[1][2][3][4][5]. ARK2C regulates motor neuron axon extension in the dorsal forelimb, modulates cellular processes such as nervous system development, and enhances BMP and TGFβ signaling by promoting the ubiquitination and subsequent degradation of inhibitory proteins like SMAD6, SMAD7, SKI, and SNON[2][3][5]. It operates through a unique Ub-dependent mechanism, forming complexes with E2-Ub and free ubiquitin, which stabilizes the transfer-active conformation for efficient substrate ubiquitination[2][4]. ARK2C and its close paralog Arkadia (RNF111) have disease relevance in several cancer types and developmental syndromes, and may participate in the SUMO-ubiquitin crosstalk by preferentially targeting SUMO-modified substrates[5]. This target is a bona fide E3 ligase, a regulatory node in key signaling pathways rather than a classical receptor, and represents a potential—though unproven—therapeutic target for modulating TGFβ/BMP signaling in disease contexts.

Other names

ARK2CRNF165ARKL2RNF111L2Ark2CRING finger protein 165E3 ubiquitin-protein ligase RNF165

Drugs would act by modulating ubiquitin ligase activity—affecting ubiquitination and degradation of specific substrates (e.g. SMAD inhibitors, SUMO-modified proteins)