The DOI matches its Crossref record; 41 of the 42 references it cites were found in a registry or an index.
An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor
Open accessAbstract
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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“EGFR mutations are expected to activate the EGFR by destabilizing the inactive form of EGFR without ligand stimulation [7–9].”
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Cites
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368
Untangling the ErbB signalling network
Yarden, Y., & Sliwkowski, M. X. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35052073 · Cited by 6,974
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338
Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji055 · Cited by 2,377
The Conformational Plasticity of Protein Kinases
Huse, M., & Kuriyan, J. (2002) · Cell · doi:10.1016/s0092-8674(02)00741-9 · Cited by 1,760
Self-citationGefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways
Sordella, R., Bell, D. W., Haber, D. A., & Settleman, J. E. (2004) · Science · doi:10.1126/science.1101637 · Cited by 1,605
Stamos, J. L., Sliwkowski, M. X., & Eigenbrot, C. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207135200 · Cited by 1,594
Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex
Jeffrey, P. D., Russo, A. A., Polyák, K., Gibbs, E., Hurwitz, J., Massagué, J., & Pavletich, N. P. (1995) · Nature · doi:10.1038/376313a0 · Cited by 1,455
Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains
Ogiso, H., Ishitani, R., Nureki, O., Fukai, S., Yamanaka, M., Kim, J.-H., Saito, K., Sakamoto, A., Inoue, M., Shirouzu, M., et al. (2002) · Cell · doi:10.1016/s0092-8674(02)00963-7 · Cited by 1,227
Cited by
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Cell Signaling by Receptor Tyrosine Kinases
Lemmon, M. A., & Schlessinger, J. (2010) · Cell · doi:10.1016/j.cell.2010.06.011 · Cited by 7,929
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Wee, P., & Wang, Z. (2017) · Cancers · doi:10.3390/cancers9050052 · Cited by 2,027
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
Taipale, M., Jarosz, D. F., & Lindquist, S. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2918 · Cited by 1,818
Emerging functions of the EGFR in cancer
Sigismund, S., Avanzato, D., & Lanzetti, L. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12155 · Cited by 1,552
Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 125
- Issue
- 6
- Pages
- 1137-1149
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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