The Shc-binding site of the betac subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis.
Tyrosine and serine phosphorylation of the common beta chain (beta(c)) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors is widely viewed as a general mechanism that provides positive inputs by coupling the receptor to signaling pathways that stimulate several cellular functions. We show here that despite the known action of Tyr577 in beta(c) to recruit Shc-PI-3 kinase (PI3K) pathway members, Tyr577 plays, surprisingly, a negative regulatory role in cell function, and that this is mediated, at least in part, through the uncoupling of SH2-containing inositol 5'-phosphatase (SHIP) from beta(c). Fetal liver cells from beta(c)/beta(IL-3)(-/-) mice expressing human GM-CSF receptor alpha chain and beta(c) Tyr577Phe mutant showed enhanced colony formation and expansion of progenitor cells in response to GM-CSF. Dissection of these activities revealed that basal survival was increased, as well as cytokine-stimulated proliferation. As expected, the recruitment and activation of Shc was abolished, but interestingly, Gab-2 and Akt phosphorylation increased. Significantly, the activation of PI3K was enhanced and prolonged, accompanied by loss of SHIP activity. These results reveal a previously unrecognized negative signaling role for Tyr577 in beta(c) and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signaling as well as survival and proliferation.
Ramshaw
Hayley S
HS
Cytokine Receptor Laboratory, Division of Human Immunology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, Australia.
Guthridge
Mark A
MA
Stomski
Frank C
FC
Barry
Emma F
EF
Ooms
Lisa
L
Mitchell
Christina A
CA
Begley
C Glenn
CG
Lopez
Angel F
AF
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D053648:Cytokine Receptor Common beta Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D053648:Cytokine Receptor Common beta Subunit; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases