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Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells

Author

Listed:
  • Charlène Niogret

    (University of Lausanne)

  • S. M. Shahjahan Miah

    (Brown University Alpert Medical School)

  • Giorgia Rota

    (University of Lausanne)

  • Nicolas P. Fonta

    (University of Lausanne
    Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine)

  • Haiping Wang

    (University of Lausanne
    University of Lausanne)

  • Werner Held

    (University of Lausanne)

  • Walter Birchmeier

    (Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Society)

  • Veronica Sexl

    (University of Veterinary Medicine)

  • Wentian Yang

    (Rhode Island Hospital and Brown University Alpert Medical School)

  • Eric Vivier

    (Aix Marseille Université, Inserm, CNRS, Avenue de Luminy
    Service d’Immunologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille
    Innate Pharma Research Labs., Innate Pharma)

  • Ping-Chih Ho

    (University of Lausanne
    University of Lausanne)

  • Laurent Brossay

    (Brown University Alpert Medical School)

  • Greta Guarda

    (University of Lausanne
    Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine)

Abstract

The phosphatase Shp-2 was implicated in NK cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear. Here we show, using mice conditionally deficient for Shp-2 in the NK lineage, that NK cell development and responsiveness are largely unaffected. Instead, we find that Shp-2 serves mainly to enforce NK cell responses to activation by IL-15 and IL-2. Shp-2-deficient NK cells have reduced proliferation and survival when treated with high dose IL-15 or IL-2. Mechanistically, Shp-2 deficiency hampers acute IL-15 stimulation-induced raise in glycolytic and respiration rates, and causes a dramatic defect in ERK activation. Moreover, inhibition of the ERK and mTOR cascades largely phenocopies the defect observed in the absence of Shp-2. Together, our data reveal a critical function of Shp-2 as a molecular nexus bridging acute IL-15 signaling with downstream metabolic burst and NK cell expansion.

Suggested Citation

  • Charlène Niogret & S. M. Shahjahan Miah & Giorgia Rota & Nicolas P. Fonta & Haiping Wang & Werner Held & Walter Birchmeier & Veronica Sexl & Wentian Yang & Eric Vivier & Ping-Chih Ho & Laurent Brossay, 2019. "Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09431-3
    DOI: 10.1038/s41467-019-09431-3
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    Cited by:

    1. Panayiotis Anastasiou & Christopher Moore & Sareena Rana & Mona Tomaschko & Claire E. Pillsbury & Andrea Castro & Jesse Boumelha & Edurne Mugarza & Sophie Carné Trécesson & Ania Mikolajczak & Cristina, 2024. "Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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