title: G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase.
abstract: 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.
authors.affiliation: Department of Pediatrics and Cellular and Molecular Biology, Children's Memorial Hospital and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Futami
authors.forename: Quan-Sheng
authors.initials: QS
authors.lastname: Zhu
authors.forename: Zakary L
authors.initials: ZL
authors.lastname: Whichard
authors.forename: Ling
authors.initials: L
authors.lastname: Xia
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002469:Cell Separation; D004789:Enzyme Activation / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D016188:Receptors, Granulocyte Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11