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Mechanistic insights into the activation of oncogenic forms of EGF receptor

Nature Structural & Molecular Biology volume 18, pages 1388–1393 (2011)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly activated by mutation in non–small cell lung cancer. The mechanism of this oncogenic activation is not completely understood, but in contrast to that of the wild-type EGFR, it is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have mainly relied on cell-based assays or isolated kinase domain measurements. Here we show, using purified, near full-length human EGFR proteins (tEGFRs), that two oncogenic mutants are fully active independently of EGF and highly resistant to the therapeutic and endogenous inhibitors cetuximab, lapatinib and MIG6. Based on the pattern of inhibition and the effects of additional asymmetric kinase dimer interface mutations, we propose that these oncogenic EGFR mutants drive and strongly depend on the formation of the asymmetric kinase dimer for activation, which has implications for drug design and cancer treatment strategies.

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Figure 1: Activation and inhibition mechanism for WT EGFR and the expression and purification strategy for mutant tEGFRs.
Figure 2: MIG6 seg 1+2 interacts with WT- and mutant tEGFRs.
Figure 3: Role of the asymmetric dimer interface for oncogenic EGFR activation.

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Acknowledgements

We thank the US National Institutes of Health (GM099321 to D.J.L. and CA074305 to P.A.C.) for financial support and A. Mildvan and J. Stivers for helpful discussions.

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Authors and Affiliations

  1. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Zhihong Wang, Mary Katherine Tarrant, Sarah Head & Philip A Cole

  2. Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Patti A Longo, Kwangsoo Kim & Daniel J Leahy

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  1. Zhihong Wang
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Contributions

Z.W., D.J.L. and P.A.C. conceived of the project and designed the research. Z.W., M.K.T., P.A.L., K.K. and S.H. conducted experiments. All authors helped analyze the results and wrote the paper.

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Correspondence to Daniel J Leahy or Philip A Cole.

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Supplementary Figures 1–6 and Supplementary Methods (PDF 749 kb)

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Wang, Z., Longo, P., Tarrant, M. et al. Mechanistic insights into the activation of oncogenic forms of EGF receptor. Nat Struct Mol Biol 18, 1388–1393 (2011). https://doi.org/10.1038/nsmb.2168

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