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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3582-3590. Prepublished online as a Blood First Edition Paper on July 16, 2007; DOI 10.1182/blood-2007-01-070391. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-01-070391v1 110/10/3582    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ramshaw, H. S. Articles by Lopez, A. F. Search for Related Content PubMed PubMed Citation Articles by Ramshaw, H. S. Articles by Lopez, A. F. Related Collections Signal Transduction Chemokines, Cytokines, and Interleukins Hematopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS The Shc-binding site of the ßc subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis Hayley S. Ramshaw1, Mark A. Guthridge2,3, Frank C. Stomski1, Emma F. Barry2, Lisa Ooms4, Christina A. Mitchell4, C. Glenn Begley5, and Angel F. Lopez1 1 Cytokine Receptor Laboratory, Division of Human Immunology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, Australia; 2 Cell Growth and Differentiation Laboratory, Division of Human Immunology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, Australia; 3 Department of Medicine, University of Adelaide, Adelaide, Australia; 4 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia; and 5 Amgen, Thousand Oaks, CA Tyrosine and serine phosphorylation of the common ß chain (ßc) 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 ßc 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 ßc. Fetal liver cells from ßc/ßIL-3–/– mice expressing human GM-CSF receptor chain and ßc 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 ßc and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signaling as well as survival and proliferation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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