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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1942-1949. Prepublished online as a Blood First Edition Paper on May 14, 2007; DOI 10.1182/blood-2007-03-079699. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2007-03-079699v1 110/6/1942    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 Ong, C. J. Articles by Mui, A. L.-F. Search for Related Content PubMed PubMed Citation Articles by Ong, C. J. Articles by Mui, A. L.-F. Related Collections Hematopoiesis and Stem Cells Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells Christopher J. Ong1,8,9, Andrew Ming-Lum1,2,8, Matt Nodwell3, Ali Ghanipour1,2,8, Lu Yang3, David E. Williams3, Joseph Kim1,2,8, Loutfig Demirjian1,2,8, Pooran Qasimi1,2,8, Jens Ruschmann6,7, Li-Ping Cao7, Kewei Ma4, Stephen W. Chung1,8, Vincent Duronio4, Raymond J. Andersen3, Gerald Krystal5,7, and Alice L.-F. Mui1,2,8 Departments of1 Surgery, 2 Biochemistry and Molecular Biology, 3 Chemistry and Earth and Ocean Sciences, 4 Medicine, 5 Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; 6 Fachbereich Biologie, Chemie, Pharmazie, Takustr, Freie Universität-Berlin, Germany; 7 Terry Fox Laboratory, British Columbia Cancer Agency; 8 Immunity and Infection Research Centre, Vancouver, Canada; 9 Prostate Centre at Vancouver General Hospital, Vancouver Coastal Health Research Institute, Vancouver, Canada Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation, and survival, pharmacologic inhibitors targeting components of the PI3K pathway are actively being developed as therapeutics for the treatment of inflammatory disorders and cancer. These targeted drugs inhibit the activity of either PI3K itself or downstream protein kinases. However, a previously unexplored, alternate strategy is to activate the negative regulatory phosphatases in this pathway. The SH2-containing inositol-5'-phosphatase SHIP1 is a normal physiologic counter-regulator of PI3K in immune/hematopoietic cells that hydrolyzes the PI3K product phosphatidylinositiol-3,4,5-trisphosphate (PIP3). We now describe the identification and characterization of potent and specific small-molecule activators of SHIP1. These compounds represent the first small-molecule activators of a phosphatase, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophage and mast cells. Mechanism of activation studies with these compounds suggest that they bind a previously undescribed, allosteric activation domain within SHIP1. Furthermore, in vivo administration of these compounds was protective in mouse models of endotoxemia and acute cutaneous anaphylaxis, suggesting that SHIP1 agonists could be used therapeutically to inhibit the PI3K pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Solinas, G. Germano, A. Mantovani, and P. Allavena Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation J. Leukoc. Biol., November 1, 2009; 86(5): 1065 - 1073. [Abstract] [Full Text] [PDF] A. Jacquel, N. Benikhlef, J. Paggetti, N. Lalaoui, L. Guery, E. K. Dufour, M. Ciudad, C. Racoeur, O. Micheau, L. Delva, et al. Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages Blood, October 22, 2009; 114(17): 3633 - 3641. [Abstract] [Full Text] [PDF] J. Zhang, S. F. Walk, K. S. Ravichandran, and J. C. Garrison Regulation of the Src Homology 2 Domain-containing Inositol 5'-Phosphatase (SHIP1) by the Cyclic AMP-dependent Protein Kinase J. Biol. Chem., July 24, 2009; 284(30): 20070 - 20078. [Abstract] [Full Text] [PDF] D. J. Haddon, F. Antignano, M. R. Hughes, M.-R. Blanchet, L. Zbytnuik, G. Krystal, and K. M. McNagny SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo J. Immunol., July 1, 2009; 183(1): 228 - 236. [Abstract] [Full Text] [PDF] S. J. Harris, R. V. Parry, J. Westwick, and S. G. Ward Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes J. Biol. Chem., February 1, 2008; 283(5): 2465 - 2469. [Abstract] [Full Text] [PDF]

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