Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.

Cervical cancer is the most common gynecologic cancer. Autophagy is involved in the progression of CCa. ULK1 is a crucial kinase in autophagy initiation. However, few studies have investigated the role of ULK1 phosphorylation at tyrosine residues in the progression of CCa, and the underlying mechanism remains elusive. In this study, we demonstrated that JAK2 is a novel upstream kinase that phosphorylates ULK1 at the tyrosine site. JAK2 interacts with and phosphorylates ULK1 at Tyr1007. The phosphorylation of ULK1 at Y1007 increases its activity and stability, activates autophagy, and promotes the progression of CCa. We further showed that the phosphorylation of ULK1 at Y1007 is a predictive marker of CCa patient outcome. Furthermore, we identified SRPK1 as a potential downstream substrate of ULK1 to promote the progression of CCa. Our research sheds light on the molecular mechanism of CCa progression, through JAK2/ULK1 axis, and emphasizes the phosphorylation of ULK1 at Y1007 as a predictor of CCa.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by rapid progression and exceptionally poor prognosis. Identifying novel molecular drivers and therapeutic targets is urgently needed. This study reports a previously unrecognized MET–YANK2 signaling axis that drives glioma progression. Analysis of glioma patient samples reveals that high co‑expression of MET and YANK2 is positively correlated and significantly associated with poor survival outcomes. Mechanistically, MET directly phosphorylates YANK2 at tyrosine 282 (Y282), a conserved residue critical for maintaining YANK2 protein stability. This phosphorylation event prevents SUMOylation mediated proteasomal degradation of YANK2, thereby enhancing its oncogenic function. Functional assays demonstrate that YANK2 phosphorylation promotes GBM cell proliferation and tumor growth both in vitro and in vivo. Conversely, loss of this phosphorylation or enhanced SUMOylation at lysine residues K8 and K148 markedly suppresses YANK2 oncogenic activity. Through structure based screening, rutin, a natural flavonoid compound, is identified as a potent direct binder of YANK2. Rutin treatment effectively inhibits YANK2 kinase activity, reduces downstream p70S6K phosphorylation, and selectively suppresses proliferation of YANK2 high GBM cells. Importantly, rutin exhibits synergistic effects with temozolomide (TMZ), significantly inhibiting tumor growth and prolonging survival in YANK2 overexpressing orthotopic glioma models. Collectively, these findings establish YANK2 as a novel prognostic biomarker and a promising therapeutic target, and highlight rutin as a potential chemosensitizer for biomarker driven combination therapy in glioma.

The YANK (yet another novel kinase) family, which includes YANK1 (serine/threonine kinase 32A), YANK2 (serine/threonine kinase 32B), and YANK3 (serine/threonine kinase 32C), is a class of serine/threonine protein kinases capable of transferring a γ-phosphate group from adenosine triphosphate to a serine or threonine residue to initiate protein function and catalyze phosphorylation of the substrate protein. Overexpression of these kinases is reported in various diseases, such as essential tremor, Alzheimer’s disease, and glioma. The YANK family is considered to have “druggable” potential, and a comprehensive review of the existing studies on YANK is helpful for obtaining a more intuitive understanding of its research status. The following section introduces the YANK family from 4 perspectives: sequence characteristics, biological functions, relationships with diseases, and upstream and downstream regulation.