Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases

PLoS Biol. 2021 Mar 8;19(3):e3001063. doi: 10.1371/journal.pbio.3001063. eCollection 2021 Mar.


The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Asthma / metabolism
  • Asthma / physiopathology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CSK Tyrosine-Protein Kinase / metabolism*
  • Cell Proliferation
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
  • MAP Kinase Signaling System / physiology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / physiology


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SPRY2 protein, human
  • CSK Tyrosine-Protein Kinase
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Protein Serine-Threonine Kinases
  • Spry2 protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 3