Blood Journal
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Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells

  1. Antonio Bilancio,
  2. Klaus Okkenhaug,
  3. Montserrat Camps,
  4. Juliet L. Emery,
  5. Thomas Ruckle,
  6. Christian Rommel, and
  7. Bart Vanhaesebroeck
  1. 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.

Abstract

Mouse gene–targeting studies have documented a central role of the p110δ 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 p110δ-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110δ in BCR signaling. p110δ 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 α/β (GSK3α/β) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110δ catalytic activity. Resting B cells with inactive p110δ 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). p110δ 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 p110δ mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110δ as a drug target in autoimmune diseases in which B cells play a crucial role.

  • Submitted July 28, 2005.
  • Accepted September 8, 2005.
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