SEARCH:   Advanced

This Article Full Text Full Text (PDF) 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 Carver, D. J. Articles by Ravichandran, K. S. Search for Related Content PubMed PubMed Citation Articles by Carver, D. J. Articles by Ravichandran, K. S. Related Collections Apoptosis Signal Transduction Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2000, Vol. 96, No. 4, pp. 1449-1456 IMMUNOBIOLOGY SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization Deborah Jeannean Carver, Mohammad Javad Aman, and Kodimangalam S. Ravichandran From the Department of Pediatrics, Beirne B. Carter Center for Immunology Research, and Department of Microbiology, University of Virginia, Charlottesville, VA. Activation of the serine/threonine kinase Akt and the regulation of its activation are recognized as critical in controlling proliferative/survival signals via many hematopoietic receptors. In B lymphocytes, the B-cell receptor (BCR)-mediated activation of Akt is attenuated by co-cross-linking of BCR with the inhibitory receptor FcRIIB1, and the binding of the SH2 domain-containing inositol phosphatase, SHIP, to FcRIIB1. Because SHIP dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3) and activation of Akt requires PIP3, the destruction of this phospholipid has been proposed as the mechanism for Akt inhibition. However, upstream kinases that activate Akt, such as PDK1, also require PIP3 for activation. In this report, we addressed whether SHIP inhibits Akt directly at the level of Akt recruitment to the membrane, indirectly through PDK recruitment/phosphorylation of Akt, or both. We generated stable B-cell lines expressing a regulatable, but constitutively membrane-bound Akt that still required PDK-dependent phosphorylation for activation. Several lines of evidence suggested that activation of this membrane-targeted Akt is not inhibited by FcRIIB1/SHIP and that PDK is not a target for SHIP-mediated inhibition. These data demonstrate that SHIP inhibits Akt primarily through regulation of Akt membrane localization. We also observed during these studies that FcRIIB1/SHIP does not inhibit p70S6k activation, even though several other PIP3-dependent events were down-regulated. Because the enhanced activation of Akt in the absence of SHIP correlates with hyperproliferation in the myeloid lineage, our data have implications for SHIP and Akt-dependent regulation of proliferation in the hematopoietic lineage. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. A. Rider, C. E.G. Havenith, R. de Ridder, J. Schuurman, C. Favre, J. C. Cooper, S. Walker, O. Baadsgaard, S. Marschner, J. G.J. vandeWinkel, et al. A Human CD4 Monoclonal Antibody for the Treatment of T-Cell Lymphoma Combines Inhibition of T-Cell Signaling by a Dual Mechanism with Potent Fc-Dependent Effector Activity Cancer Res., October 15, 2007; 67(20): 9945 - 9953. [Abstract] [Full Text] [PDF] D. J. Carver, B. Gaston, K. deRonde, and L. A. Palmer Akt-Mediated Activation of HIF-1 in Pulmonary Vascular Endothelial Cells by S-Nitrosoglutathione Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 255 - 263. [Abstract] [Full Text] [PDF] T. Tarasenko, H. K. Kole, A. W. Chi, M. M. Mentink-Kane, T. A. Wynn, and S. Bolland T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses PNAS, July 3, 2007; 104(27): 11382 - 11387. [Abstract] [Full Text] [PDF] M. Gururajan, T. Dasu, S. Shahidain, C. D. Jennings, D. A. Robertson, V. M. Rangnekar, and S. Bondada Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth J. Immunol., January 1, 2007; 178(1): 111 - 121. [Abstract] [Full Text] [PDF] C. A. Doughty, B. F. Bleiman, D. J. Wagner, F. J. Dufort, J. M. Mataraza, M. F. Roberts, and T. C. Chiles Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth Blood, June 1, 2006; 107(11): 4458 - 4465. [Abstract] [Full Text] [PDF] C. D. Helgason, J. Antonchuk, C. Bodner, and R. K. Humphries Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice Blood, November 15, 2003; 102(10): 3541 - 3547. [Abstract] [Full Text] [PDF] Z.-Y. Huang, S. Hunter, M.-K. Kim, Z. K. Indik, and A. D. Schreiber The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fc{gamma} receptors Fc{gamma}RIIB and Fc{gamma}RIIA J. Leukoc. Biol., June 1, 2003; 73(6): 823 - 829. [Abstract] [Full Text] [PDF] F. A. Barry and J. M. Gibbins Protein Kinase B Is Regulated in Platelets by the Collagen Receptor Glycoprotein VI J. Biol. Chem., April 5, 2002; 277(15): 12874 - 12878. [Abstract] [Full Text] [PDF] S. Tridandapani, K. Siefker, J.-L. Teillaud, J. E. Carter, M. D. Wewers, and C. L. Anderson Regulated Expression and Inhibitory Function of Fcgamma RIIb in Human Monocytic Cells J. Biol. Chem., February 8, 2002; 277(7): 5082 - 5089. [Abstract] [Full Text] [PDF] S. Gardai, B. B. Whitlock, C. Helgason, D. Ambruso, V. Fadok, D. Bratton, and P. M. Henson Activation of SHIP by NADPH Oxidase-stimulated Lyn Leads to Enhanced Apoptosis in Neutrophils J. Biol. Chem., February 8, 2002; 277(7): 5236 - 5246. [Abstract] [Full Text] [PDF] S. F. Walk, M. Alexander, B. Maier, M.-L. Hammarskjold, D. M. Rekosh, and K. S. Ravichandran Design and Use of an Inducibly Activated Human Immunodeficiency Virus Type 1 Nef To Study Immune Modulation J. Virol., January 15, 2001; 75(2): 834 - 843. [Abstract] [Full Text] M. E. March, D. M. Lucas, M. J. Aman, and K. S. Ravichandran p135 Src Homology 2 Domain-containing Inositol 5'-Phosphatase (SHIPbeta ) Isoform Can Substitute for p145 SHIP in Fcgamma RIIB1-mediated Inhibitory Signaling in B Cells J. Biol. Chem., September 22, 2000; 275(39): 29960 - 29967. [Abstract] [Full Text] [PDF] O. Malbec, C. Schmitt, P. Bruhns, G. Krystal, W. H. Fridman, and M. Daeron Src Homology 2 Domain-containing Inositol 5-Phosphatase 1 Mediates Cell Cycle Arrest by Fcgamma RIIB J. Biol. Chem., August 3, 2001; 276(32): 30381 - 30391. [Abstract] [Full Text] [PDF] X. Pesesse, V. Dewaste, F. De Smedt, M. Laffargue, S. Giuriato, C. Moreau, B. Payrastre, and C. Erneux The Src Homology 2 Domain Containing Inositol 5-Phosphatase SHIP2 Is Recruited to the Epidermal Growth Factor (EGF) Receptor and Dephosphorylates Phosphatidylinositol 3,4,5-Trisphosphate in EGF-stimulated COS-7 Cells J. Biol. Chem., July 20, 2001; 276(30): 28348 - 28355. [Abstract] [Full Text] [PDF]

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2000 by American Society of Hematology         Online ISSN: 1528-0020