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https://hdl.handle.net/2440/50099
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Type: | Journal article |
Title: | The Shc-binding site of the β[c] subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis |
Other Titles: | The Shc-binding site of the beta[c] subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis |
Author: | Ramshaw, H. Guthridge, M. Stomski, F. Barry, E. Ooms, L. Mitchell, C. Begley, C. Lopez, A. |
Citation: | Blood, 2007; 110(10):3582-3590 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2007 |
ISSN: | 0006-4971 0006-4971 |
Abstract: | 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 αchain 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. |
Keywords: | Liver Bone Marrow Cells Hematopoietic Stem Cells Cells, Cultured Animals Mice, Knockout Humans Mice Phosphoric Monoester Hydrolases Adaptor Proteins, Signal Transducing Phosphoproteins Transduction, Genetic Hematopoiesis Cell Survival Binding Sites Phosphorylation Point Mutation Cytokine Receptor Common beta Subunit Shc Signaling Adaptor Proteins Phosphatidylinositol 3-Kinases Inositol Polyphosphate 5-Phosphatases Src Homology 2 Domain-Containing, Transforming Protein 1 |
Description: | Copyright © 2007 by American Society of Hematology |
DOI: | 10.1182/blood-2007-01-070391 |
Published version: | http://dx.doi.org/10.1182/blood-2007-01-070391 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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