Abstract
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.
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Acknowledgements
YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. Our work is supported by research grants from the Goldhirsh Foundation, the US National Cancer Institute (NCI; CA072981 to YY, CA118705, CA141556 and U54-CA112967 to FMW), the Israel Science Foundation and Dr Miriam and Sheldon G Adelson Medical Research Foundation.
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Pines, G., Huang, P., Zwang, Y. et al. EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism. Oncogene 29, 5850–5860 (2010). https://doi.org/10.1038/onc.2010.313
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DOI: https://doi.org/10.1038/onc.2010.313
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