title: PDK1 regulates B cell differentiation and homeostasis.
abstract: Successful B cell differentiation and prevention of cell transformation depends on balanced and fine-tuned activation of cellular signaling pathways. The phosphatidyl inositol-3 kinase (PI3K) signaling pathway has emerged as a major regulator of B lymphocyte homeostasis and function. Phosphoinositide-dependent protein kinase-1 (PDK1) is the pivotal node in the PI3K pathway, regulating the stability and activity of downstream AGC kinases (including Akt, RSK, S6K, SGK, and PKC). Although the importance of PI3K activity in B cell differentiation is well documented, the role of PDK1 and other downstream effectors is underexplored. Here we used inducible and stage-specific gene targeting approaches to elucidate the role of PDK1 in early and peripheral B cell differentiation. PDK1 ablation enhanced cell cycle entry and apoptosis of IL-7-dependent pro-B cells, blocking Ig synthesis and B cell maturation. PDK1 also was essential for the survival and activation of peripheral B cells via regulation of PKC and Akt-dependent downstream effectors, such as GSK3α/β and Foxo1. We found that PDK1 deletion strongly impaired B cell receptor (BCR) signaling, but IL-4 costimulation was sufficient to restore BCR-induced proliferation. IL-4 also normalized PKCβ activation and hexokinase II expression in BCR-stimulated cells, suggesting that this signaling pathway can act independent of PDK1 to support B cell growth. In summary, our results demonstrate that PDK1 is indispensable for B cell survival, proliferation, and growth regulation.
authors: Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors: Gisele V
authors: GV
authors: Baracho
authors: Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors: Matthew H
authors: MH
authors: Cato
authors: Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors: Zilu
authors: Z
authors: Zhu
authors: Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors: Olav R
authors: OR
authors: Jaren
authors: BIOSS Centre for Biological Signalling Studies and Department of Molecular Immunology, Bio III, Faculty of Biology, University of Freiburg and Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors: Elias
authors: E
authors: Hobeika
authors: BIOSS Centre for Biological Signalling Studies and Department of Molecular Immunology, Bio III, Faculty of Biology, University of Freiburg and Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors: Michael
authors: M
authors: Reth
authors: Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and robert@sanfordburnham.org.
authors: Robert C
authors: RC
authors: Rickert
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D001853:Bone Marrow / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D011947:Receptors, Antigen, B-Cell; D018121:Receptors, Cytokine; D019869:Phosphatidylinositol 3-Kinases; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse