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Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor

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 incompletely understood but, in contrast to the WT EGFR, is proposed to be independent of kinase domain dimerizati...

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Autores principales: Wang, Zhihong, Longo, Patti A., Tarrant, Mary Katherine, Kim, Kwangsoo, Head, Sarah, Leahy, Daniel J., Cole, Philip A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230693/
https://www.ncbi.nlm.nih.gov/pubmed/22101934
http://dx.doi.org/10.1038/nsmb.2168
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author Wang, Zhihong
Longo, Patti A.
Tarrant, Mary Katherine
Kim, Kwangsoo
Head, Sarah
Leahy, Daniel J.
Cole, Philip A.
author_facet Wang, Zhihong
Longo, Patti A.
Tarrant, Mary Katherine
Kim, Kwangsoo
Head, Sarah
Leahy, Daniel J.
Cole, Philip A.
author_sort Wang, Zhihong
collection PubMed
description 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 incompletely understood but, in contrast to the WT EGFR, is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have largely relied on cell-based assays or isolated kinase domain measurements. Here we show using purified, near full-length EGFR proteins (tEGFRs) that two oncogenic mutants are fully active in the absence of EGF and highly resistant to the known 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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spelling pubmed-32306932012-06-01 Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor Wang, Zhihong Longo, Patti A. Tarrant, Mary Katherine Kim, Kwangsoo Head, Sarah Leahy, Daniel J. Cole, Philip A. Nat Struct Mol Biol Article 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 incompletely understood but, in contrast to the WT EGFR, is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have largely relied on cell-based assays or isolated kinase domain measurements. Here we show using purified, near full-length EGFR proteins (tEGFRs) that two oncogenic mutants are fully active in the absence of EGF and highly resistant to the known 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. 2011-11-20 /pmc/articles/PMC3230693/ /pubmed/22101934 http://dx.doi.org/10.1038/nsmb.2168 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Zhihong
Longo, Patti A.
Tarrant, Mary Katherine
Kim, Kwangsoo
Head, Sarah
Leahy, Daniel J.
Cole, Philip A.
Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor
title Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor
title_full Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor
title_fullStr Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor
title_full_unstemmed Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor
title_short Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor
title_sort mechanistic insights into the activation of oncogenic forms of egf receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230693/
https://www.ncbi.nlm.nih.gov/pubmed/22101934
http://dx.doi.org/10.1038/nsmb.2168
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