EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism
Author(s)
Pines, G; Zwang, Y; Yarden, Y; Huang, P. H.; White, Forest M.
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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.
Date issued
2010-08Department
Massachusetts Institute of Technology. Department of Biological EngineeringJournal
Oncogene
Publisher
Nature Publishing Group
Citation
Pines, G, P H Huang, Y Zwang, F M White, and Y Yarden. “EGFRvIV: a Previously Uncharacterized Oncogenic Mutant Reveals a Kinase Autoinhibitory Mechanism.” Oncogene 29, no. 43 (August 2, 2010): 5850–5860.
Version: Author's final manuscript
ISSN
0950-9232
1476-5594