Cited by 1,650HER2/EGFR in Cancer ResearchProtein Kinase Regulation and GTPase SignalingLung Cancer Treatments and Mutations

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An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor

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Zhang, Xuewu, Gureasko, Jodi, Shen, Kui, Cole, Philip A., Kuriyan, John·2006·Cell

DOI 10.1016/j.cell.2006.05.013

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Abstract

The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization.

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Authors: Zhang, X., Gureasko, J., Shen, K., Cole, P. A., & Kuriyan, J.
Affiliations: Howard Hughes Medical Institute (US)
Johns Hopkins University (US)
Corresponding author: Kuriyan, John
ORCID: Zhang, Xuewu
Shen, Kui
Cole, Philip A.
Kuriyan, John
Venue: Cell
Publisher: Elsevier BV
Published: 2006-06
Volume: 125
Issue: 6
Pages: 1137-1149
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2006.05.013
OpenAlex: W2100794900
Cited by: 1,650
References: 42
Citations by year: 2026: 81 · 2025: 70 · 2024: 67 · 2023: 91 · 2022: 76 · 2021: 75 · 2020: 83 · 2019: 77 · 2018: 78 · 2017: 60 · 2016: 66 · 2015: 103 · 2014: 120 · 2013: 95 · 2012: 76
FWCI: 40.87
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2639 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01-CA74305, R01CA096504, R01-CA96504, R01CA074305)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: epidermal growth factor receptor, allosteric activation, autoinhibition, receptor dimerization, activation loop, asymmetric dimer, cyclin-dependent kinases, Src kinase, C-terminal lobe, receptor tyrosine kinase
MeSH terms: Allosteric Regulation, Amino Acid Sequence, Animals, Enzyme Activation, Humans, Leucine, Models, Molecular, Molecular Sequence Data, Mutation, Phosphorylation, Protein Conformation, Protein Structure, Tertiary, Crystallography, X-Ray, Cyclin-Dependent Kinases, src-Family Kinases, Dimerization, NIH 3T3 Cells, Mice, ErbB Receptors

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An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor

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