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Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9573-8. doi: 10.1073/pnas.1314562111. Epub 2014 Jun 16.

PDK1 regulates B cell differentiation and homeostasis.

Author information

1
Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
2
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.
3
Program on Immunity and Pathogenesis, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and robert@sanfordburnham.org.

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.

PMID:
24979759
PMCID:
PMC4084446
DOI:
10.1073/pnas.1314562111
[Indexed for MEDLINE]
Free PMC Article

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