EGFR Phosphorylates Tumor-Derived EGFRvIII Driving STAT3/5 and Progression in Glioblastoma

EGFRvIII, a frequently occurring mutation in primary glioblastoma, results in a protein product that cannot bind ligand, but signals constitutively. Deducing how EGFRvIII causes transformation has been difficult because of autocrine and paracrine loops triggered by EGFRvIII alone or in heterodimers...

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Published inCancer cell Vol. 24; no. 4; pp. 438 - 449
Main Authors Fan, Qi-Wen, Cheng, Christine K., Gustafson, W. Clay, Charron, Elizabeth, Zipper, Petra, Wong, Robyn A., Chen, Justin, Lau, Jasmine, Knobbe-Thomsen, Christiane, Weller, Michael, Jura, Natalia, Reifenberger, Guido, Shokat, Kevan M., Weiss, William A.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 14.10.2013
Subjects
Alleles
Brain Neoplasms - metabolism
Cell Line, Tumor
Cell Nucleus - metabolism
Disease Progression
Gene Expression Regulation, Neoplastic
Glioblastoma - metabolism
Humans
Mutation
Neoplasm Transplantation
Phosphorylation
Receptor, Epidermal Growth Factor - metabolism
Signal Transduction
STAT3 Transcription Factor - metabolism
STAT5 Transcription Factor - metabolism
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Summary:EGFRvIII, a frequently occurring mutation in primary glioblastoma, results in a protein product that cannot bind ligand, but signals constitutively. Deducing how EGFRvIII causes transformation has been difficult because of autocrine and paracrine loops triggered by EGFRvIII alone or in heterodimers with wild-type EGFR. Here, we document coexpression of EGFR and EGFRvIII in primary human glioblastoma that drives transformation and tumorigenesis in a cell-intrinsic manner. We demonstrate enhancement of downstream STAT signaling triggered by EGFR-catalyzed phosphorylation of EGFRvIII, implicating EGFRvIII as a substrate for EGFR. Subsequent phosphorylation of STAT3 requires nuclear entry of EGFRvIII and formation of an EGFRvIII-STAT3 nuclear complex. Our findings clarify specific oncogenic signaling relationships between EGFR and EGFRvIII in glioblastoma. •Rare cells within human glioblastomas express both EGFR and tumor-derived EGFRvIII•Coexpression of EGFR and EGFRvIII shows enhanced transformation in vitro and in vivo•EGFR promotes unidirectional activation of EGFRvIII, converging to activate STAT3•Coexpression of EGFR and EGFRvIII leads to a nuclear complex between vIII and STAT3
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ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.09.004