MET-mediated phosphorylation of YANK2 at Y282 inhibits NEDD4L-dependent SUMOylation and degradation, promoting chemoresistance in glioblastoma

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Abstract
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.
Funding Information
  • National Natural Science Foundation of China (Grant No. 82260528)
  • International Cooperation Projects of Henan Province (Grant No. 242102520018)

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