Niogret, Charlène Miah, S. M. Shahjahan Rota, Giorgia Fonta, Nicolas P. Wang, Haiping Held, Werner Birchmeier, Walter Sexl, Veronica Yang, Wentian Vivier, Eric Ho, Ping-Chih Brossay, Laurent Guarda, Greta 2019-03-29 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. application/pdf https://susi.usi.ch/global/documents/318906 https://localhost:5000/ark:/12658/srd1318906 https://susi.usi.ch/documents/318906/files/Niogret_NatCommun_2019.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-019-09431-3 info:eu-repo/semantics/altIdentifier/ark/12658/srd1318906 info:eu-repo/semantics/openAccess CC BY Nature communications. - 2019, vol. 10, p. 1444 Interleukins NK cells Signal transduction TOR signalling info:eu-repo/classification/udc/57/59 Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells http://purl.org/coar/resource_type/c_6501