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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 (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 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. Social Bookmarking                   What's this? Submitted July 31, 2003 Accepted September 29, 2003 A novel SHP-1/Grb2-dependent mechanism of negative regulation of cytokine receptor signaling Parham Minoo, Maryam Mohsen Zadeh, Robert Rottapel, Jean-Jacques Lebrun, and Suhad Ali* Department of Medicine, Division of Hematology, Molecular Oncology Group, McGill University, Montreal, PQ, Canada Division of Experimental Therapeutics, Ontario Cancer Institute, Princess Margaret Hospital, Departments of Immunology and Medicine, University of Toronto, Toronto, ON, Canada Department of Medicine, Molecular Endocrinology, McGill University, Montreal, PQ, Canada * Corresponding author; email: suhad.ali{at}muhc.mcgill.ca. SHP-1, an 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 downregulates the Jak2 (Janus kinase-2)/Stat5 (signal transducer and activator of transcription-5) pathway downstream of the prolactin (PRLR) and the erythropoietin (EPOR) receptors in a catalytic activity independent manner. Structural/functional analysis of SHP-1 defined that the C-terminal tyrosine residues (Y278, Y303, Y538, Y566) within Grb-2 binding motif to be responsible for serving 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 downregulate PRL-induced Stat5 activation. Altogether, 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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