Cancers 2011, 3(2), 2032-2049; doi:10.3390/cancers3022032
Article

Glioma Specific Extracellular Missense Mutations in the First Cysteine Rich Region of Epidermal Growth Factor Receptor (EGFR) Initiate Ligand Independent Activation

1 Oncogenic Signaling Laboratory, Monash Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia 2 Tumor Targeting Laboratory, Ludwig Institute for Cancer Research, Heidelberg, VIC 3084, Australia 3 CSIRO Division of Materials Science and Engineering, Parkville, VIC 3052, Australia These authors contributed equally to this work. Current address: CSIRO Division of Materials Science and Engineering, Parkville, VIC 3052, Australia.
* Author to whom correspondence should be addressed.
Received: 25 February 2011; in revised form: 29 March 2011 / Accepted: 7 April 2011 / Published: 18 April 2011
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
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Abstract: The epidermal growth factor receptor (EGFR) is overexpressed or mutated in glioma. Recently, a series of missense mutations in the extracellular domain (ECD) of EGFR were reported in glioma patients. Some of these mutations clustered within a cysteine-rich region of the EGFR targeted by the therapeutic antibody mAb806. This region is only exposed when EGFR activates and appears to locally misfold during activation. We expressed two of these mutations (R324L and E330K) in NR6 mouse fibroblasts, as they do not express any EGFR-related receptors. Both mutants were autophosphorylated in the absence of ligand and enhanced cell survival and anchorage-independent and xenograft growth. The ECD truncation that produces the de2-7EGFR (or EGFRvIII), the most common EGFR mutation in glioma, generates a free cysteine in this same region. Using a technique optimized for detecting disulfide-bonded dimers, we definitively demonstrated that the de2-7EGFR is robustly dimerized and that ablation of the free cysteine prevents dimerization and activation. Modeling of the R324L mutation suggests it may cause transient breaking of disulfide bonds, leading to similar disulfide-bonded dimers as seen for the de2-7EGFR. These ECD mutations confirm that the cysteine-rich region of EGFR around the mAb806 epitope has a significant role in receptor activation.
Keywords: EGFR; de2-7EGFR; extracellular domain mutation; autoactivation; dimerization; disulfide bond; free cysteine

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MDPI and ACS Style

Ymer, S.I.; Greenall, S.A.; Cvrljevic, A.; Cao, D.X.; Donoghue, J.F.; Epa, V.C.; Scott, A.M.; Adams, T.E.; Johns, T.G. Glioma Specific Extracellular Missense Mutations in the First Cysteine Rich Region of Epidermal Growth Factor Receptor (EGFR) Initiate Ligand Independent Activation. Cancers 2011, 3, 2032-2049.

AMA Style

Ymer SI, Greenall SA, Cvrljevic A, Cao DX, Donoghue JF, Epa VC, Scott AM, Adams TE, Johns TG. Glioma Specific Extracellular Missense Mutations in the First Cysteine Rich Region of Epidermal Growth Factor Receptor (EGFR) Initiate Ligand Independent Activation. Cancers. 2011; 3(2):2032-2049.

Chicago/Turabian Style

Ymer, Susie I.; Greenall, Sameer A.; Cvrljevic, Anna; Cao, Diana X.; Donoghue, Jacqui F.; Epa, V. Chandana; Scott, Andrew M.; Adams, Timothy E.; Johns, Terrance G. 2011. "Glioma Specific Extracellular Missense Mutations in the First Cysteine Rich Region of Epidermal Growth Factor Receptor (EGFR) Initiate Ligand Independent Activation." Cancers 3, no. 2: 2032-2049.

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