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Blood, 15 January 2006, Vol. 107, No. 2, pp. 642-650. Prepublished online as a Blood First Edition Paper on September 22, 2005; DOI 10.1182/blood-2005-07-3041. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-3041v1 107/2/642    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 Bilancio, A. Articles by Vanhaesebroeck, B. Search for Related Content PubMed PubMed Citation Articles by Bilancio, A. Articles by Vanhaesebroeck, B. Related Collections Immunobiology Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Key role of the p110 isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110 function in B cells Antonio Bilancio, Klaus Okkenhaug, Montserrat Camps, Juliet L. Emery, Thomas Ruckle, Christian Rommel, and Bart Vanhaesebroeck From the Ludwig Institute for Cancer Research, London, United Kingdom; Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge, United Kingdom; Serono Pharmaceutical Research Institute, Serono International, Geneva, Switzerland; and the Department of Biochemistry and Molecular Biology, University College London, United Kingdom. Mouse gene–targeting studies have documented a central role of the p110 isoform of phosphoinositide 3-kinase (PI3K) in B-cell development and function. A defect in B-cell antigen receptor (BCR) signaling is key to this B-cell phenotype. Here we further characterize this signaling defect and report that a p110-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110 in BCR signaling. p110 activity is indispensable for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B (PKB), forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase (p70 S6K), with modest effects on the phosphorylation of glycogen synthase kinase 3 / (GSK3/) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110 catalytic activity. Resting B cells with inactive p110 fail to enter the cell cycle, correlating with an incapacity to up-regulate the expression of cyclins D2, A, and E, and to phosphorylate the retinoblastoma protein (Rb). p110 is also critical for interleukin 4 (IL-4)–induced phosphorylation of Akt/PKB and FOXO3a, and protection from apoptosis. Taken together, these data show that defects observed in p110 mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110 as a drug target in autoimmune diseases in which B cells play a crucial role. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Knock-outs and inhibitors: one and the same? Zachary A. Knight and Kevan M. Shokat Blood 2006 107: 420-421. [Full Text] [PDF] This article has been cited by other articles: C. A. Durand, K. Hartvigsen, L. Fogelstrand, S. Kim, S. Iritani, B. Vanhaesebroeck, J. L. Witztum, K. D. Puri, and M. R. Gold Phosphoinositide 3-Kinase p110{delta} Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses J. Immunol., November 1, 2009; 183(9): 5673 - 5684. [Abstract] [Full Text] [PDF] D. Liu, T. Zhang, A. J. Marshall, K. Okkenhaug, B. Vanhaesebroeck, and J. E. Uzonna The p110{delta} Isoform of Phosphatidylinositol 3-Kinase Controls Susceptibility to Leishmania major by Regulating Expansion and Tissue Homing of Regulatory T Cells J. Immunol., August 1, 2009; 183(3): 1921 - 1933. [Abstract] [Full Text] [PDF] F. Chiarini, F. Fala, P. L. Tazzari, F. Ricci, A. Astolfi, A. Pession, P. Pagliaro, J. A. McCubrey, and A. M. Martelli Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia Cancer Res., April 15, 2009; 69(8): 3520 - 3528. [Abstract] [Full Text] [PDF] E. A. Papakonstanti, O. Zwaenepoel, A. Bilancio, E. Burns, G. E. Nock, B. Houseman, K. Shokat, A. J. Ridley, and B. Vanhaesebroeck Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages J. Cell Sci., December 15, 2008; 121(24): 4124 - 4133. [Abstract] [Full Text] [PDF] E. Zebedin, O. Simma, C. Schuster, E. M. Putz, S. Fajmann, W. Warsch, E. Eckelhart, D. Stoiber, E. Weisz, J. A. Schmid, et al. Leukemic challenge unmasks a requirement for PI3K{delta} in NK cell-mediated tumor surveillance Blood, December 1, 2008; 112(12): 4655 - 4664. [Abstract] [Full Text] [PDF] S. Sauer, L. Bruno, A. Hertweck, D. Finlay, M. Leleu, M. Spivakov, Z. A. Knight, B. S. Cobb, D. Cantrell, E. O'Connor, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR PNAS, June 3, 2008; 105(22): 7797 - 7802. [Abstract] [Full Text] [PDF] T. Doi, K. Obayashi, T. Kadowaki, H. Fujii, and S. Koyasu PI3K is a negative regulator of IgE production Int. Immunol., April 1, 2008; 20(4): 499 - 508. [Abstract] [Full Text] [PDF] K. Ali, M. Camps, W. P. Pearce, H. Ji, T. Ruckle, N. Kuehn, C. Pasquali, C. Chabert, C. Rommel, and B. Vanhaesebroeck Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110{delta} but Not p110{gamma} Promotes Optimal Allergic Responses In Vivo J. Immunol., February 15, 2008; 180(4): 2538 - 2544. [Abstract] [Full Text] [PDF] M. L. Janas, D. Hodson, Z. Stamataki, S. Hill, K. Welch, L. Gambardella, L. C. Trotman, P. P. Pandolfi, E. Vigorito, and M. Turner The Effect of Deleting p110{delta} on the Phenotype and Function of PTEN-Deficient B Cells J. Immunol., January 15, 2008; 180(2): 739 - 746. [Abstract] [Full Text] [PDF] H. Ji, F. Rintelen, C. Waltzinger, D. Bertschy Meier, A. Bilancio, W. Pearce, E. Hirsch, M. P. Wymann, T. Ruckle, M. Camps, et al. Inactivation of PI3K{gamma} and PI3K{delta} distorts T-cell development and causes multiple organ inflammation Blood, October 15, 2007; 110(8): 2940 - 2947. [Abstract] [Full Text] [PDF] P. R. Cutillas and B. Vanhaesebroeck Quantitative Profile of Five Murine Core Proteomes Using Label-free Functional Proteomics Mol. Cell. Proteomics, September 1, 2007; 6(9): 1560 - 1573. [Abstract] [Full Text] [PDF] B. Geering, P. R. Cutillas, G. Nock, S. I. Gharbi, and B. Vanhaesebroeck Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers PNAS, May 8, 2007; 104(19): 7809 - 7814. [Abstract] [Full Text] [PDF] C. Riou, B. Yassine-Diab, J. Van grevenynghe, R. Somogyi, L. D. Greller, D. Gagnon, S. Gimmig, P. Wilkinson, Y. Shi, M. J. Cameron, et al. Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells J. Exp. Med., January 22, 2007; 204(1): 79 - 91. [Abstract] [Full Text] [PDF]

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