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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1061-1068. Prepublished online as a Blood First Edition Paper on September 28, 2006; DOI 10.1182/blood-2006-05-023556. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-05-023556v1 109/3/1061    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 Orr, S. J. Articles by Johnston, J. A. Search for Related Content PubMed PubMed Citation Articles by Orr, S. J. Articles by Johnston, J. A. Related Collections Signal Transduction Immunobiology Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover Selinda J. Orr1, Nuala M. Morgan1, Joanne Elliott1, James F. Burrows1, Christopher J. Scott2, Daniel W. McVicar3, and James A. Johnston1 1 Infection and Immunity, Centre for Cancer Research and Cell Biology, Queens University, Belfast, United Kingdom; 2 Molecular Therapeutics, School of Pharmacy, Queens University, Belfast, United Kingdom; 3 Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute–Frederick Cancer Research and Development Center, (NCI-FCRDC), Frederick, MD CD33 is a member of the sialic acid–binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to -CD33 therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Pairing SOCS with CD33 Edward D. Ball Blood 2007 109: 852. [Full Text] [PDF] This article has been cited by other articles: J. Elliott SOCS3 in Liver Regeneration and Hepatocarcinoma Mol. Interv., February 1, 2008; 8(1): 19 - 21. [Abstract] [Full Text] [PDF]

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