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RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation

Author

Listed:
  • Berta Casar

    (Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III)

  • Andrew P. Badrock

    (The University of Manchester)

  • Iñaki Jiménez

    (Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria)

  • Imanol Arozarena

    (Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria
    Navarrabiomed-FMS IDISNA, Pamplona)

  • Paula Colón-Bolea

    (Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria)

  • L. Francisco Lorenzo-Martín

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III
    Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca
    Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca)

  • Irene Barinaga-Rementería

    (The University of Manchester)

  • Jorge Barriuso

    (The University of Manchester)

  • Vincenzo Cappitelli

    (Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria)

  • Daniel J. Donoghue

    (University of California)

  • Xosé R. Bustelo

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III
    Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca
    Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca)

  • Adam Hurlstone

    (The University of Manchester)

  • Piero Crespo

    (Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III)

Abstract

RAS GTPases are frequently mutated in human cancer. H- and NRAS isoforms are distributed over both plasma-membrane and endomembranes, including the Golgi complex, but how this organizational context contributes to cellular transformation is unknown. Here we show that RAS at the Golgi is selectively activated by apoptogenic stimuli and antagonizes cell survival by suppressing ERK activity through the induction of PTPRκ, which targets CRAF for dephosphorylation. Consistently, in contrast to what occurs at the plasma-membrane, RAS at the Golgi cannot induce melanoma in zebrafish. Inactivation of PTPRκ, which occurs frequently in human melanoma, often coincident with TP53 inactivation, accelerates RAS-ERK pathway-driven melanomagenesis in zebrafish. Likewise, tp53 disruption in zebrafish facilitates oncogenesis driven by RAS from the Golgi complex. Thus, RAS oncogenic potential is strictly dependent on its sublocalization, with Golgi complex-located RAS antagonizing tumor development.

Suggested Citation

  • Berta Casar & Andrew P. Badrock & Iñaki Jiménez & Imanol Arozarena & Paula Colón-Bolea & L. Francisco Lorenzo-Martín & Irene Barinaga-Rementería & Jorge Barriuso & Vincenzo Cappitelli & Daniel J. Dono, 2018. "RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05941-8
    DOI: 10.1038/s41467-018-05941-8
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