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Blood, 1 February 2004, Vol. 103, No. 3, pp. 820-827. Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-06-1999. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-06-1999v1 103/3/820    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Guthridge, M. A. Articles by Lopez, A. F. Search for Related Content PubMed PubMed Citation Articles by Guthridge, M. A. Articles by Lopez, A. F. Related Collections Hematopoiesis and Stem Cells Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS The phosphoserine-585–dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-B and induction of bcl-2 Mark A. Guthridge, Emma F. Barry, Fernando A. Felquer, Barbara J. McClure, Frank C. Stomski, Hayley Ramshaw, and Angel F. Lopez From the Cytokine Receptor Laboratory, Department of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia. We have recently identified a novel mechanism of hematopoietic cell survival that involves site-specific serine phosphorylation of the common beta subunit (c) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors. However, the downstream components of this pathway are not known, nor is its relationship to survival signals triggered by tyrosine phosphorylation of the receptor clear. We have now found that phosphorylation of Ser585 of c in response to GM-CSF recruited 14-3-3 and phosphatidyl inositol 3-OH kinase (PI 3-kinase) to the receptor, while phosphorylation of the neighboring Tyr577 within this "viability domain" promoted the activation of both Src homology and collagen (Shc) and Ras. These are independent processes as demonstrated by the intact reactivity of phosphospecific anti-Ser585 and anti-Tyr577 antibodies on the cytotoxic T-lymphocyte–ecotrophic retroviral receptor neomycin (CTL-EN) mutants cTyr577Phe and cSer585Gly, respectively. Importantly, while mutants in which either Ser585 (cSer585Gly) or all tyrosines (cF8) were substituted showed a defect in Akt phosphorylation, nuclear factor B (NF-B) activation, bcl-2 induction, and cell survival, the mutant cTyr577Phe was defective in Shc, Ras, and extracellular signal-related kinase (ERK) activation, but supported CTL-EN cell survival in response to GM-CSF. These results demonstrate that both serine and tyrosine phosphorylation pathways play a role in hematopoietic cell survival, are initially independent of each other, and converge on NF-B to promote bcl-2 expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. R. Hercus, D. Thomas, M. A. Guthridge, P. G. Ekert, J. King-Scott, M. W. Parker, and A. F. Lopez The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease Blood, August 13, 2009; 114(7): 1289 - 1298. [Abstract] [Full Text] [PDF] E. F. Barry, F. A. Felquer, J. A. Powell, L. Biggs, F. C. Stomski, A. Urbani, H. Ramshaw, P. Hoffmann, M. C. Wilce, M. A. Grimbaldeston, et al. 14-3-3:Shc Scaffolds Integrate Phosphoserine and Phosphotyrosine Signaling to Regulate Phosphatidylinositol 3-Kinase Activation and Cell Survival J. Biol. Chem., May 1, 2009; 284(18): 12080 - 12090. [Abstract] [Full Text] [PDF] S. A. Didichenko, N. Spiegl, T. Brunner, and C. A. Dahinden IL-3 induces a Pim1-dependent antiapoptotic pathway in primary human basophils Blood, November 15, 2008; 112(10): 3949 - 3958. [Abstract] [Full Text] [PDF] T. Shen, S. Kim, J.-s. Do, L. Wang, C. Lantz, J. F. Urban, G. Le Gros, and B. Min T cell-derived IL-3 plays key role in parasite infection-induced basophil production but is dispensable for in vivo basophil survival Int. Immunol., September 1, 2008; 20(9): 1201 - 1209. [Abstract] [Full Text] [PDF] A. Lonic, E. F. Barry, C. Quach, B. Kobe, N. Saunders, and M. A. Guthridge Fibroblast Growth Factor Receptor 2 Phosphorylation on Serine 779 Couples to 14-3-3 and Regulates Cell Survival and Proliferation Mol. Cell. Biol., May 15, 2008; 28(10): 3372 - 3385. [Abstract] [Full Text] [PDF] F.-T. Mu, R. K. Andrews, J. F. Arthur, A. D. Munday, S. L. Cranmer, S. P. Jackson, F. C. Stomski, A. F. Lopez, and M. C. Berndt A functional 14-3-3{zeta}-independent association of PI3-kinase with glycoprotein Ib{alpha}, the major ligand-binding subunit of the platelet glycoprotein Ib-IX-V complex Blood, May 1, 2008; 111(9): 4580 - 4587. [Abstract] [Full Text] [PDF] W. Li, S.-i. Kashiwamura, H. Ueda, A. Sekiyama, and H. Okamura Protection of CD8+ T cells from activation-induced cell death by IL-18 J. Leukoc. Biol., July 1, 2007; 82(1): 142 - 151. [Abstract] [Full Text] [PDF] M. Rosas, P. F. Dijkers, C. L. Lindemans, J.-W. J. Lammers, L. Koenderman, and P. J. Coffer IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with {beta}-catenin relocalization J. Leukoc. Biol., July 1, 2006; 80(1): 186 - 195. [Abstract] [Full Text] [PDF] D. Thomas, J. Powell, S.-H. Lee, A. F. Lopez, and G. Mark Primary Acute Myeloid Leukemic Blasts Display Constitutive Serine 585 Phosphorylation within the 14-3-3 Binding Motif of the GM-CSF/IL-3 Receptor Required for Survival Signalling. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 70 - 70. [Abstract] H.-S. Suh, M.-O. Kim, and S. C. Lee Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Signaling and Microglial Proliferation by Anti-CD45RO: Role of Hck Tyrosine Kinase and Phosphatidylinositol 3-Kinase/Akt J. Immunol., March 1, 2005; 174(5): 2712 - 2719. [Abstract] [Full Text] [PDF]

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