PDK1 regulates B cell differentiation and homeostasis

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / immunology
  • 3-Phosphoinositide-Dependent Protein Kinases / metabolism*
  • Animals
  • B-Lymphocytes / immunology*
  • Blotting, Western
  • Bone Marrow / immunology*
  • Cell Differentiation / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Homeostasis / immunology*
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Cytokine / metabolism
  • Statistics, Nonparametric


  • Receptors, Antigen, B-Cell
  • Receptors, Cytokine
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Pdpk1 protein, mouse