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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.


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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 ßcIL-3–/– mice expressing human GM-CSF receptor {alpha} 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.


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