RASD2 Drives Renal Clear Cell Carcinoma Progression via RAF1 (Ser338) Phosphorylation.

Clear cell renal cell carcinoma (ccRCC) is a highly aggressive malignancy with limited treatment options. Although RASD2, which encodes a Ras-related GTP-binding protein, has been linked to melanoma progression, its role in ccRCC remains unclear. In this study, we systematically investigated the oncogenic functions and mechanisms of RASD2 in ccRCC. Clinically, RASD2 was significantly overexpressed in tumor tissues compared with adjacent normal tissues and correlated with poor patient prognosis. Functional studies demonstrated that RASD2 promotes proliferation, migration, and invasion of the ccRCC cells in vitro, findings further supported by xenograft models in nude mice. Mechanistically, RASD2 activated the P38/ERK-MAPK pathway, and inhibition experiments confirmed its necessity for RASD2-driven oncogenesis. Through co-immunoprecipitation and LC-MS/MS, we identified RAF1 as a key binding partner. RASD2 enhanced RAF1 phosphorylation at Ser338, thereby activating the P38/ERK-MAPK pathway. RAF1 phosphorylation at Ser338 was critical for ccRCC cell growth, migration, and invasion. The RAF1 inhibitor BAY43-9006 reduced p-RAF1 (Ser338)/RAF1 levels, suppressed ccRCC proliferation, migration, and invasion in vitro, and significantly inhibited tumor growth in vivo. These findings identify RASD2 as a novel oncoprotein that promotes ccRCC tumorigenesis through p-RAF1 (Ser338)-mediated P38/ERK-MAPK activation, suggesting RAF1 inhibition as a promising therapeutic strategy for ccRCC patients.