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

Nat Commun. 2019 Mar 29;10(1):1444. doi: 10.1038/s41467-019-09431-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Cell Count
  • Cell Proliferation / drug effects
  • Cell Size / drug effects
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Integrases / metabolism
  • Interleukin-15 / pharmacology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / physiology
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Receptors, Interleukin-15 / metabolism*
  • TOR Serine-Threonine Kinases / metabolism


  • Antigens, Ly
  • Interleukin-15
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Receptors, Interleukin-15
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Cre recombinase
  • Integrases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse