G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase

Blood. 2011 Jul 28;118(4):1077-86. doi: 10.1182/blood-2009-12-261636. Epub 2011 Jun 2.


Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. After G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatiotemporal manner. The dephosphorylation of phospho-Lyn Tyr507 was abrogated in Shp2-deficient cells transfected with the G-CSF receptor but intact in cells expressing phosphatase-defective Shp2. Auto-phosphorylation of Lyn Tyr396 was impaired in cells treated with Gab2 siRNA. The constitutively activated Shp2E76A directed the dephosphorylation of phospho-Lyn Tyr507 in vitro. Tyr507 did not undergo dephosphorylation in G-CSF-stimulated cells expressing a mutant Gab2 unable to bind Shp2. We propose that Gab2 forms a complex with Lyn and after G-CSF stimulation, Gab2 recruits Shp2, which dephosphorylates phospho-Lyn Tyr507, leading to Lyn activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Separation
  • Enzyme Activation / physiology*
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Receptors, Granulocyte Colony-Stimulating Factor / metabolism*
  • Signal Transduction / physiology*
  • Transfection
  • src-Family Kinases / metabolism*


  • Adaptor Proteins, Signal Transducing
  • GAB2 protein, human
  • Receptors, Granulocyte Colony-Stimulating Factor
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11