EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism.

TitleEGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism.
Publication TypeJournal Article
Year of Publication2010
AuthorsPines, G, Huang, PH, Zwang, Y, White, FM, Yarden, Y
Date Published2010 Oct 28
KeywordsAnimals, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Female, Genes, erbB-1, Glioblastoma, Humans, Immunoprecipitation, Mass Spectrometry, Mice, Mice, Nude, Mutation, NIH 3T3 Cells, Signal Transduction

Tumor cells often subvert normal regulatory mechanisms of signal transduction. This study shows this principle by studying yet uncharacterized mutants of the epidermal growth factor receptor (EGFR) previously identified in glioblastoma multiforme, which is the most aggressive brain tumor in adults. Unlike the well-characterized EGFRvIII mutant form, which lacks a portion of the ligand-binding cleft within the extracellular domain, EGFRvIVa and EGFRvIVb lack internal segments distal to the intracellular tyrosine kinase domain. By constructing the mutants and by ectopic expression in naive cells, we show that both mutants confer an oncogenic potential in vitro, as well as tumorigenic growth in animals. The underlying mechanisms entail constitutive receptor dimerization and basal activation of the kinase domain, likely through a mechanism that relieves a restraining molecular fold, along with stabilization due to association with HSP90. Phosphoproteomic analyses delineated the signaling pathways preferentially engaged by EGFRvIVb-identified unique substrates. This information, along with remarkable sensitivities to tyrosine kinase blockers and to a chaperone inhibitor, proposes strategies for pharmacological interception in brain tumors harboring EGFRvIV mutations.

Alternate JournalOncogene
PubMed ID20676128
PubMed Central IDPMC3634975
Grant ListCA072981 / CA / NCI NIH HHS / United States
CA118705 / CA / NCI NIH HHS / United States
CA141556 / CA / NCI NIH HHS / United States
R37 CA072981 / CA / NCI NIH HHS / United States
U54-CA112967 / CA / NCI NIH HHS / United States