Journal
ONCOGENE
Volume 29, Issue 43, Pages 5850-5860Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.313
Keywords
EGFR mutations; glioblastoma; growth factor; signal transduction; tyrosine kinase
Funding
- Goldhirsh Foundation
- US National Cancer Institute (NCI) [CA072981, CA118705, CA141556, U54-CA112967]
- Israel Science Foundation
- Dr Miriam and Sheldon G Adelson Medical Research Foundation
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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. Phospho-proteomic 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. Oncogene (2010) 29, 5850-5860; doi: 10.1038/onc.2010.313; published online 2 August 2010
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