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  Enhanced dimerization drives ligand-independent activity of mutant EGFR in lung cancer.

Valley, C. C., Arndt-Jovin, D. J., Karedla, N., Steinkamp, M. P., Chizhik, A. I., Hlavacek, W. S., et al. (2015). Enhanced dimerization drives ligand-independent activity of mutant EGFR in lung cancer. Molecular Biology of the Cell, 26(22), 4087-4099. doi:10.1091/mbc.E15-05-0269.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-935A-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-5174-8
Genre: Journal Article

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 Creators:
Valley, C. C., Author
Arndt-Jovin, D. J.1, Author              
Karedla, N., Author
Steinkamp, M. P., Author
Chizhik, A. I., Author
Hlavacek, W. S., Author
Wilson, B. S., Author
Lidke, K. A., Author
Lidke, D. S., Author
Affiliations:
1Emeritus Group Laboratory of Cellular Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_578629              

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 Abstract: Mutations within the epidermal growth factor receptor (EGFR/erbB1/Her1) are often associated with tumorigenesis. In particular, a number of EGFR mutants that demonstrate ligand-independent signaling are common in non-small cell lung cancer (NSCLC), including kinase domain mutations L858R (also called L834R) and exon 19 deletions (e.g. ΔL747-P753insS) which collectively make up nearly 90% of mutations in NSCLC. The molecular mechanisms by which these mutations confer constitutive activity remain unresolved. Using multiple subdiffraction-limit imaging modalities, we reveal the altered receptor structure and interaction kinetics of NSCLC-associated EGFR mutants. We applied two-color single quantum dot tracking to quantify receptor dimerization kinetics on living cells and show that, in contrast to wild type EGFR, mutants are capable of forming stable, ligand-independent dimers. Two-color super-resolution localization microscopy confirmed ligand-independent aggregation of EGFR mutants. Live cell FRET measurements revealed that the L858R kinase mutation alters ectodomain structure such that unliganded mutant EGFR adopts an extended, dimerization-competent conformation. Finally, mutation of the putative dimerization arm confirmed a critical role for ectodomain engagement in ligand-independent signaling. These data support a model in which dysregulated activity of NSCLC-associated kinase mutants is driven by coordinated interactions involving both the kinase and extracellular domains that lead to enhanced dimerization.

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Language(s): eng - English
 Dates: 2015-09-022015-11-05
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1091/mbc.E15-05-0269
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Title: Molecular Biology of the Cell
Source Genre: Journal
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Pages: - Volume / Issue: 26 (22) Sequence Number: - Start / End Page: 4087 - 4099 Identifier: -