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The Shc-binding site of the beta(c) subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis
journal contribution
posted on 2007-11-15, 00:00 authored by H Ramshaw, Mark GuthridgeMark Guthridge, Frank C Stomski, Emma F Barry, Lisa Ooms, Christina A Mitchell, C Glenn Begley, A F LopezAbstract
Tyrosine and serine phosphorylation of the common β chain (βc) 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 βc 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 βc. Fetal liver cells from βc/βIL-3−/− mice expressing human GM-CSF receptor α chain and βc 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 βc and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signaling as well as survival and proliferation.
Tyrosine and serine phosphorylation of the common β chain (βc) 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 βc 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 βc. Fetal liver cells from βc/βIL-3−/− mice expressing human GM-CSF receptor α chain and βc 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 βc and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signaling as well as survival and proliferation.
History
Journal
BLOODVolume
110Issue
10Pagination
3582 - 3590Publisher
AMER SOC HEMATOLOGYLocation
United StatesPublisher DOI
ISSN
0006-4971eISSN
1528-0020Language
EnglishPublication classification
C1 Refereed article in a scholarly journalUsage metrics
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