Journal article

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

  • Niogret, Charlène Department of Biochemistry, University of Lausanne, Switzerland
  • Miah, S. M. Shahjahan Department of Molecular Microbiology and Immunology and Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, USA
  • Rota, Giorgia Department of Biochemistry, University of Lausanne, Switzerland
  • Fonta, Nicolas P. Department of Biochemistry, University of Lausanne, Switzerland - Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Wang, Haiping Department of Oncology UNIL CHUV, University of Lausanne, Switzerland - Department of Fundamental Oncology, University of Lausanne, Switzerland
  • Held, Werner Department of Oncology UNIL CHUV, University of Lausanne, Switzerland
  • Birchmeier, Walter Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany
  • Sexl, Veronica Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
  • Yang, Wentian Department of Orthopaedics, Rhode Island Hospital and Brown University Alpert Medical School, Providence, USA
  • Vivier, Eric Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France - Service d’Immunologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, France - Innate Pharma Research Labs., Innate Pharma, Marseille, France
  • Ho, Ping-Chih Department of Oncology UNIL CHUV, University of Lausanne, Switzerland - Department of Fundamental Oncology, University of Lausanne, Switzerland
  • Brossay, Laurent Department of Molecular Microbiology and Immunology and Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, USA
  • Guarda, Greta Department of Biochemistry, University of Lausanne, Switzerland - Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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    29.03.2019
Published in:
  • Nature communications. - 2019, vol. 10, p. 1444
English 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.
Language
  • English
Classification
Biology, life sciences
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https://susi.usi.ch/usi/documents/318906
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