title: EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma.
abstract: 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.
authors.affiliation: Department of Neurology, University of California, San Francisco, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA. Electronic address: qiwen.fan@ucsf.edu.
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Fan
authors.forename: Christine K
authors.initials: CK
authors.lastname: Cheng
authors.forename: W Clay
authors.initials: WC
authors.lastname: Gustafson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Charron
authors.forename: Petra
authors.initials: P
authors.lastname: Zipper
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Wong
authors.forename: Justin
authors.initials: J
authors.lastname: Chen
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lau
authors.forename: Christiane
authors.initials: C
authors.lastname: Knobbe-Thomsen
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Natalia
authors.initials: N
authors.lastname: Jura
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000483:Alleles; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C410723:epidermal growth factor receptor VIII; C512478:EGFR protein, human; D066246:ErbB Receptors