Mitogen-activated protein kinase 10 suppresses non-small cell lung cancer metastasis through phosphorylation-dependent ubiquitination of keratin 16

Keratin 16 (KRT16), an intermediate filament protein frequently overexpressed in metastatic cancers, is primarily regulated at the transcriptional level. In this study, we identified mitogen-activated protein kinase 10 (MAPK10) as a pivotal kinase that phosphorylates KRT16 at specific residues, namely Ser356 and Ser397. This phosphorylation event triggers RNF213-mediated ubiquitination, subsequently leading to proteasomal degradation of KRT16. In vitro experiments demonstrated that MAPK10 knockdown significantly enhanced the migration and invasion capabilities of non-small cell lung cancer (NSCLC) cells. Conversely, the activation of p38 MAPK by Anisomycin treatment rescued metastatic suppression in MAPK10-deficient mice at a dose of 10 mg/kg. (p < 0.001). Clinically, our analysis of 36 NSCLC specimens revealed a significant inverse correlation between MAPK10 expression and KRT16 levels (R² = 0.7538, p < 0.0001). Furthermore, high MAPK10 expression was associated with a favorable prognosis in NSCLC patients, as evidenced by a hazard ratio (HR) of 0.42 (95 % confidence interval: 0.28-0.63). Collectively, these findings establish the MAPK10/KRT16/RNF213 axis as a promising therapeutic target and prognostic biomarker for NSCLC metastasis, providing new directions for the development of personalized treatment strategies.