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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 13, 2007 Accepted April 22, 2007 Small molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells Christopher J Ong, Andrew Ming-Lum, Matt Nodwell, Ali Ghanipour, Lu Yang, David E Williams, Joseph Kim, Loutfig Demirjian, Pooran Qasimi, Jens Ruschmann, Li-Ping Cao, Kewei Ma, Stephen W Chung, Vincent Duronio, Raymond J Andersen, Gerald Krystal, and Alice L-F. Mui* Prostate Centre at Vancouver General Hospital, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada Dept of Surgery, University of British Columbia, Vancouver, British Columbia, Canada Dept of Chemistry & Earth & Ocean Sciences, University of British Columbia, Vancouver, British Columbia, Canada Dept of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada Fachbereich Biologie, Chemie, Pharmazie, Takustr, FU-Berlin, Berlin, Germany Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada Dept of Medicine, University of British Columbia, Vancouver, British Columbia, Canada Dept of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada Immunity & Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada * Corresponding author; email: amui{at}interchange.ubc.ca. Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation and survival, pharmacological 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 physiological counter-regulator of PI3K in immune/hematopoietic cells which 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 phosphatases, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact cells macrophage and mast cells. Mechanism of activation studies with these compounds suggests 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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