Enhanced dimerization drives ligand-independent activity of mutant epidermal growth factor receptor in lung cancer

Molecular Biology of the Cell
Christopher C ValleyDiane S Lidke

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 superresolution localization microscopy confirmed ligand-independent aggregation of EGFR mutants. Live-cell Förster resonance energy transfer 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 ...Continue Reading

References

Mar 9, 2000·Nature Cell Biology·Y SakoT Yanagida
Oct 7, 2003·Molecular Cell·Antony W BurgessShigeyuki Yokoyama
Jan 6, 2004·Nature Biotechnology·Diane S LidkeThomas M Jovin
Jan 21, 2004·Proceedings of the National Academy of Sciences of the United States of America·Dawn MattoonJoseph Schlessinger
Aug 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·William PaoHarold Varmus
Feb 25, 2005·The New England Journal of Medicine·Susumu KobayashiBalázs Halmos
Sep 29, 2005·PLoS Medicine·Heidi GreulichMatthew Meyerson
Feb 24, 2007·Nature Reviews. Cancer·Sreenath V SharmaDaniel A Haber
Nov 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Kristina W Thiel, Graham Carpenter
Dec 22, 2007·Acta Oncologica·Fernando RiveraRaul Marquez
Jan 1, 2008·Proceedings of the National Academy of Sciences of the United States of America·Jennifer L Macdonald, Linda J Pike
Jan 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Cai-Hong YunMichael J Eck
Apr 17, 2008·Molecular Cancer Therapeutics·Nadia Godin-HeymannDaniel A Haber
Jul 23, 2008·Angewandte Chemie·Mike HeilemannMarkus Sauer
Mar 28, 2009·Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia·Hui K GanRodney B Luwor
Jun 30, 2009·Molecular Cell·Monica Red BrewerGraham Carpenter
Dec 5, 2009·The Journal of Biological Chemistry·Abedelnasser AbulrobLinda J Johnston
Mar 17, 2010·Journal of the American Chemical Society·Oleksandr A KucherakAndrey S Klymchenko
Apr 7, 2010·Nature Methods·Carlas S SmithKeith A Lidke
Jul 7, 2010·Cell·Mark A Lemmon, Joseph Schlessinger

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Citations

Sep 18, 2015·Molecular Biology of the Cell·Meghan McCabe PryorBridget S Wilson
Sep 1, 2017·Molecular Biology of the Cell·Samantha L SchwartzDiane S Lidke
Dec 9, 2017·Artificial Cells, Nanomedicine, and Biotechnology·Swati JhaNarendra Kumar Jain
Jul 13, 2018·The Journal of Biological Chemistry·Jennifer L Macdonald-Obermann, Linda J Pike
Jan 31, 2020·Proteins·Arangasamy Yazhini, Narayanaswamy Srinivasan
Jan 9, 2020·Molecular Biology of the Cell·Emanuel Salazar-CavazosDiane S Lidke
Jul 31, 2020·The Journal of Biological Chemistry·Patrick O ByrneDaniel J Leahy
Jul 26, 2018·Science Signaling·Arianne M BrandsmaJeanette H W Leusen
Oct 20, 2018·Nature Communications·Laura C Zanetti-DominguesMarisa L Martin-Fernandez
Mar 6, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ancilla NeuMartin Bayer
Jun 3, 2020·The Journal of Clinical Investigation·Anna VyborovaJürgen Kuball
May 10, 2017·Scientific Reports·Srinivasaraghavan KannanChandra Verma
Dec 12, 2017·PloS One·Marcia Anahi HasenahuerMaría Silvina Fornasari
May 20, 2020·Frontiers in Bioengineering and Biotechnology·Yang WangLixin Ma
Jun 6, 2019·Methods and Protocols·David T Clarke, Marisa L Martin-Fernandez
Aug 19, 2016·Chembiochem : a European Journal of Chemical Biology·Regina BilanAlyona Sukhanova
Jul 22, 2020·Annual Review of Cell and Developmental Biology·Aneta Koseska, Philippe I H Bastiaens
Nov 13, 2020·Reports of Biochemistry & Molecular Biology·Forough Abdollahzadeh, Foroogh Nejatollahi
Mar 4, 2021·Experimental & Molecular Medicine·Yeonho ChangSung Ho Ryu
May 13, 2021·Cell Death & Disease·Sonali BahlEdward Seto
Aug 15, 2017·ACS Chemical Biology·Dominic Kamps, Leif Dehmelt
Nov 26, 2021·ELife·Carolina Franco NittaDiane S Lidke

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Methods Mentioned

BETA
imaging techniques
FRET
superresolution microscopy
electron microscopy
transfection
transfections

Software Mentioned

DIPImage
Matlab
dSTORM
Mathematica
MathWorks

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