CBLB Regulates MAPK‐P38 Pathway via MAP3K9 Ubiquitination to Inhibit GBM Cell Invasion and Migration

ABSTRACT Glioma cells exhibit high invasiveness and have the ability to evade surgical resection, radiotherapy, and chemotherapy, which are major factors contributing to the challenges in effective treatment and recurrence. The ubiquitin‐proteasome system (UPS) plays a crucial role in posttranslational modification, significantly contributing to the aggressive progression of glioblastoma (GBM). This study identified the E3 ubiquitin ligase CBLB as a crucial and abnormally regulated component of the UPS in GBM, noting its significant downregulation compared to normal brain tissue and its negative correlation with malignant phenotypes and poor prognosis. Experimental studies, both in vitro and in vivo, have shown that CBLB can inhibit the migration and invasion of GBM cells. Mechanistically, CBLB directly interacts with MAP3K9 through its RING domain, leading to K48‐K63‐linked polyubiquitination at the Lys 193 site, thereby promoting MAP3K9 proteasomal‐mediated degradation. MAP3K9 downregulation suppresses MAPK‐P38 pathway activation. This study identifies CBLB as a tumor suppressor that modulates the MAPK‐P38 signaling pathway by promoting the polyubiquitination and degradation of MAP3K9, offering a new therapeutic approach for GBM treatment.