E-viri
Recenzirano
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Hu, Lulu; Shen, Dachuan; Liang, Dapeng; Shi, Ji; Song, Chunyan; Jiang, Ke; Menglin Ren; Du, Sha; Cheng, Wei; Ma, Jianmei; Li, Shao; Bi, Xiaolin; Barr, Martin P.; Fang, Zhiyou; Xu, Qing; Li, Wenbin; Piao, Haozhe; Meng, Songshu
Cancer letters, 11/2020, Letnik: 493Journal Article
Epidermal growth factor receptor (EGFR) amplification and EGFRvIII mutation drive glioblastoma (GBM) pathogenesis, but their regulation remains elusive. Here we characterized the EGFR/EGFRvIII “interactome” in GBM and identified thyroid receptor-interacting protein 13 (TRIP13), an AAA + ATPase, as an EGFR/EGFRvIII-associated protein independent of its ATPase activity. Functionally, TRIP13 augmented EGFR pathway activation and contributed to EGFR/EGFRvIII-driven GBM growth in GBM spheroids and orthotopic GBM xenograft models. Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation. Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth. Clinically, TRIP13 expression was upregulated in GBM specimens and associated with poor patient outcome. In GBM, TRIP13 localized to cell membrane and cytoplasma and exhibited oncogenic effects in vitro and in vivo, depending on EGFR signaling but not the TRIP13 ATPase activity. Collectively, our findings uncover that TRIP13 and EGFR form a feedforward loop to potentiate EGFR signaling in GBM growth and identify a previously unrecognized ATPase activity-independent mode of action of TRIP13 in GBM biology. ∙TRIP13 associates with EGFR and EGFRvIII∙TRIP13 enhances EGFR stability, activation and downstream signaling∙TRIP13 contributes to EGFR/EGFRvIII-driven GBM growth∙EGFRvIII and EGF-activated EGFR phosphorylate TRIP13∙TRIP13 is up-regulated in GBM tissues and is associated with poor prognosis
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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