Abstract

The two Ral GTPases, RalA and RalB, have crucial roles downstream Ras oncoproteins in human cancers; in particular, RalB is involved in invasion and metastasis. However, therapies targeting Ral signalling are not available yet. By a novel optogenetic approach, we found that light-controlled activation of Ral at plasma-membrane promotes the recruitment of the Wave Regulatory Complex (WRC) via its effector exocyst, with consequent induction of protrusions and invasion. We show that active Ras signals to RalB via two RalGEFs (Guanine nucleotide Exchange Factors), RGL1 and RGL2, to foster invasiveness; RalB contribution appears to be more important than that of MAPK and PI3K pathways. Moreover, on the clinical side, we uncovered a potential role of RalB in human breast cancers by determining that RalB expression at protein level increases in a manner consistent with progression toward metastasis. This work highlights the Ras-RGL1/2-RalB-exocyst-WRC axis as appealing target for novel anti-cancer strategies.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Giulia Zago

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Irina Veith

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Manish Singh

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Laetitia Fuhrmann

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Simon De Beco

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Amanda Remorino

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Saori Takaoka

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Marjorie Palmeri

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Frédérique Berger

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Nathalie Brandon

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Ahmed El Marjou

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Anne Vincent-Salomon

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Jacques Camonis

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Mathieu Coppey

    Institut Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Maria Carla Parrini

    Institut Curie, Paris, France
    For correspondence
    maria-carla.parrini@curie.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7082-9792

Funding

Fondation ARC pour la Recherche sur le Cancer (PJA 20151203371)

  • Maria Carla Parrini

Institut National de la Santé et de la Recherche Médicale (PC201530)

  • Mathieu Coppey

Agence Nationale de la Recherche (ANR-10-IDEX-0001-02 PSL)

  • Mathieu Coppey

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany

Publication history

  1. Received: July 31, 2018
  2. Accepted: October 14, 2018
  3. Accepted Manuscript published: October 15, 2018 (version 1)
  4. Version of Record published: November 9, 2018 (version 2)
  5. Version of Record updated: November 13, 2018 (version 3)

Copyright

© 2018, Zago 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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  1. Giulia Zago
  2. Irina Veith
  3. Manish Singh
  4. Laetitia Fuhrmann
  5. Simon De Beco
  6. Amanda Remorino
  7. Saori Takaoka
  8. Marjorie Palmeri
  9. Frédérique Berger
  10. Nathalie Brandon
  11. Ahmed El Marjou
  12. Anne Vincent-Salomon
  13. Jacques Camonis
  14. Mathieu Coppey
  15. Maria Carla Parrini
(2018)
RalB directly triggers invasion downstream Ras by mobilizing the Wave complex
eLife 7:e40474.
https://doi.org/10.7554/eLife.40474

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