1. Structural Biology and Molecular Biophysics
  2. Cell Biology
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Specific cancer associated mutations in the switch III-region of Ras increase tumorigenicity by nanocluster augmentation

  1. Maja Solman
  2. Alessio Ligabue
  3. Olga Blazevits
  4. Alok Jaiswal
  5. Yong Zhou
  6. Hong Liang
  7. Benoit Lectez
  8. Kari Kopra
  9. Camilo Guzman
  10. Harri Härmä
  11. John F Hancock
  12. Tero Aittokallio
  13. Daniel Abankwa  Is a corresponding author
  1. Åbo Akademi University, Finland
  2. University of Helsinki, Finland
  3. University of Texas Health Science Center at Houston, United States
  4. University of Turku, Finland
Research Article
  • Cited 25
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Cite this article as: eLife 2015;4:e08905 doi: 10.7554/eLife.08905

Abstract

Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.

Article and author information

Author details

  1. Maja Solman

    Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  2. Alessio Ligabue

    Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  3. Olga Blazevits

    Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  4. Alok Jaiswal

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  5. Yong Zhou

    Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hong Liang

    Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Benoit Lectez

    Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  8. Kari Kopra

    Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  9. Camilo Guzman

    Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  10. Harri Härmä

    Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  11. John F Hancock

    Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Tero Aittokallio

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  13. Daniel Abankwa

    Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland
    For correspondence
    daniel.abankwa@btk.fi
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: May 21, 2015
  2. Accepted: August 13, 2015
  3. Accepted Manuscript published: August 14, 2015 (version 1)
  4. Version of Record published: September 11, 2015 (version 2)

Copyright

© 2015, Solman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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