Gankyrin/PSMD10 Protein, Human

Gankyrin/PSMD10 protein acts as a crucial chaperone during the assembly of the 26S proteasome, specifically contributing to the formation of the PA700/19S regulatory complex (RC). In the initial step of assembling the base subcomplex, it participates in an intermediate module with PSMD10, PSMC4, PSMC5, and PAAF1, which likely associates with a module comprising PSMD5, PSMC2, PSMC1, and PSMD2. Independently of the proteasome, Gankyrin regulates EGF-induced AKT activation by inhibiting the RHOA/ROCK/PTEN pathway, resulting in prolonged AKT activation. Furthermore, it plays a pivotal role in RAS-induced tumorigenesis, acting as a proto-oncoprotein through the negative regulation of tumor suppressors RB1 and p53/TP53. Gankyrin overexpression leads to the phosphorylation and proteasomal degradation of RB1, while also regulating CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Additionally, Gankyrin facilitates the binding of MDM2 to p53/TP53 and promotes the mono- and polyubiquitination of p53/TP53 by MDM2, suggesting a role in targeting the TP53:MDM2 complex to the 26S proteasome. It is involved in p53-independent apoptosis and regulates NF-kappa-B by retaining it in the cytoplasm, binding to the NF-kappa-B component RELA and facilitating its XPO1/CRM1-mediated nuclear export.