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

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Item Type:Article
Title:Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
Creators Name:Niogret, C. and Miah, S.M.S. and Rota, G. and Fonta, N.P. and Wang, H. and Held, W. and Birchmeier, W. and Sexl, V. and Yang, W. and Vivier, E. and Ho, P.C. and Brossay, L. and Guarda, G.
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.
Keywords:Cell Count, Cell Proliferation, Cell Size, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Inbred C57BL Mice, Integrases, Interleukin-15, Interleukin-15 Receptors, Knockout Mice, Ly Antigens, Muromegalovirus, Natural Cytotoxicity Triggering Receptor 1, Natural Killer Cells, Non-Receptor Type 11 Protein Tyrosine Phosphatase, TOR Serine-Threonine Kinases, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:10
Number:1
Page Range:1444
Date:29 March 2019
Official Publication:https://doi.org/10.1038/s41467-019-09431-3
PubMed:View item in PubMed

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