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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1398-1407. Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-07-2617. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2617v1 103/4/1398    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 Minoo, P. Articles by Ali, S. Search for Related Content PubMed PubMed Citation Articles by Minoo, P. Articles by Ali, S. Related Collections Signal Transduction Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY A novel SHP-1/Grb2–dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling Parham Minoo, Maryam Mohsen Zadeh, Robert Rottapel, Jean-Jacques Lebrun, and Suhad Ali From the Department of Medicine, Division of Hematology, Molecular Oncology Group, Royal Victoria Hospital, McGill University, Montreal, QC, Canada; Division of Experimental Therapeutics, Ontario Cancer Institute, Princess Margaret Hospital, Departments of Immunology and Medicine, University of Toronto, Toronto, ON, Canada; and the Department of Medicine, Molecular Endocrinology, Royal Victoria Hospital, McGill University, Montreal, QC, Canada. SHP-1, an src homology 2 (SH2) domain containing protein tyrosine phosphatase, functions as a negative regulator of signaling downstream of cytokine receptors, receptor tyrosine kinases and receptor complexes of the immune system. Dephosphorylation of receptors and/or receptor-associated kinases has been described as the mechanism for the function of SHP-1. Here we demonstrate a novel mechanism by which SHP-1 down-regulates the Janus kinase–2 (Jak2)/signal transducer and activator of transcription-5 (Stat5) pathway downstream of the prolactin receptor (PRLR) and the erythropoietin receptor (EPOR) in a catalytic activity–independent manner. Structural/functional analysis of SHP-1 defined the C-terminal tyrosine residues (Y278, Y303, Y538, Y566) within growth factor receptor–bound protein 2 (Grb-2) binding motif to be responsible for delivering the inhibitory effects. Our results further indicate that these tyrosine residues, via recruitment of the adaptor protein Grb-2, are required for targeting the inhibitory protein suppressor of cytokine signaling–1 (SOCS-1) to Jak2 kinase. Finally, loss of SOCS-1 expression in SOCS-1–/– mouse embryonic fibroblast (MEF) cells led to attenuation in SHP-1 function to down-regulate PRL-induced Stat5 activation. All together, our results indicate that SHP-1 inhibits PRLR and EPOR signaling by recruitment and targeting of SOCS-1 to Jak2, highlighting a new mechanism of SHP-1 regulation of cytokine-receptor signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Weiss and L. T. Goodnough Anemia of Chronic Disease N. Engl. J. Med., March 10, 2005; 352(10): 1011 - 1023. [Full Text] [PDF]

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