TAOK3 promotes ccRCC progression by phosphorylating ASAP2

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by high metastatic propensity and poor clinical outcomes. Elucidating the molecular mechanisms underlying ccRCC progression is therefore essential for the development of more effective therapeutic strategies. In this study, we identified thousand and one amino acid protein kinase 3 (TAOK3) as a critical oncogenic regulator in ccRCC. TAOK3 was markedly overexpressed in ccRCC tumor tissues and cell lines. Gain- and loss-of-function assays demonstrated that TAOK3 significantly promotes ccRCC cell proliferation, migration, and invasion in vitro. Mechanistically, immunoprecipitation and immunofluorescence analyses revealed that TAOK3 interacts with ASAP2 (ArfGAP with SH3 domain, ankyrin repeat, and PH domain 2) in the cytoplasm. Mass spectrometry coupled with phosphosite prediction analysis identified four serine residues (S701, S712, S722, and S728) on ASAP2 as phosphorylation targets of putative phosphorylation sites mediated by TAOK3. These phosphorylation events were further by co-immunoprecipitation and were essential for the pro-metastatic activity of the TAOK3-ASAP2 signaling axis. Collectively, these findings reveal a previously unrecognized TAOK3-dependent phosphorylation mechanism that drives ccRCC progression, and identify the TAOK3-ASAP2 axis as a promising therapeutic target for metastatic ccRCC.