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

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. Donoghue, Xosé R. Bustelo, Adam Hurlstone () and Piero Crespo ()
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Berta Casar: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria
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
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
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05941-8

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