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EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

Author

Listed:
  • Sarah R. Needham

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Selene K. Roberts

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Anton Arkhipov

    (D.E. Shaw Research)

  • Venkatesh P. Mysore

    (D.E. Shaw Research)

  • Christopher J. Tynan

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Laura C. Zanetti-Domingues

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Eric T. Kim

    (D.E. Shaw Research)

  • Valeria Losasso

    (Science and Technology Facilities Council, Daresbury Laboratory)

  • Dimitrios Korovesis

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Michael Hirsch

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Daniel J. Rolfe

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • David T. Clarke

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

  • Martyn D. Winn

    (Science and Technology Facilities Council, Daresbury Laboratory)

  • Alireza Lajevardipour

    (Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology)

  • Andrew H. A. Clayton

    (Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology)

  • Linda J. Pike

    (Washington University School of Medicine)

  • Michela Perani

    (King’s College London, Guy’s Medical School Campus)

  • Peter J. Parker

    (King’s College London, Guy’s Medical School Campus
    The Francis Crick Institute, Protein Phosphorylation Laboratory, 44 Lincoln's Inn Fields)

  • Yibing Shan

    (D.E. Shaw Research)

  • David E. Shaw

    (D.E. Shaw Research
    Columbia University)

  • Marisa L. Martin-Fernandez

    (Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford)

Abstract

Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.

Suggested Citation

  • Sarah R. Needham & Selene K. Roberts & Anton Arkhipov & Venkatesh P. Mysore & Christopher J. Tynan & Laura C. Zanetti-Domingues & Eric T. Kim & Valeria Losasso & Dimitrios Korovesis & Michael Hirsch &, 2016. "EGFR oligomerization organizes kinase-active dimers into competent signalling platforms," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13307
    DOI: 10.1038/ncomms13307
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    Citations

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    Cited by:

    1. Michael G. Sugiyama & Aidan I. Brown & Jesus Vega-Lugo & Jazlyn P. Borges & Andrew M. Scott & Khuloud Jaqaman & Gregory D. Fairn & Costin N. Antonescu, 2023. "Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Shwetha Srinivasan & Raju Regmi & Xingcheng Lin & Courtney A. Dreyer & Xuyan Chen & Steven D. Quinn & Wei He & Matthew A. Coleman & Kermit L. Carraway & Bin Zhang & Gabriela S. Schlau-Cohen, 2022. "Ligand-induced transmembrane conformational coupling in monomeric EGFR," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Gyunghee Jo & Jeomil Bae & Ho Jeong Hong & Ah-reum Han & Do-Kyun Kim & Seon Pyo Hong & Jung A Kim & Sangkyu Lee & Gou Young Koh & Ho Min Kim, 2021. "Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    4. R. Sumanth Iyer & Sarah R. Needham & Ioannis Galdadas & Benjamin M. Davis & Selene K. Roberts & Rico C. H. Man & Laura C. Zanetti-Domingues & David T. Clarke & Gilbert O. Fruhwirth & Peter J. Parker &, 2024. "Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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