PDK1 regulates B cell differentiation and homeostasis

16.06.2014

Baracho GV, Cato MH, Zhu Z, Jaren OR, Hobeika E, Reth M, Rickert RC.

Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9573-8

Proc Natl Acad Sci U S A.        online article

The phosphatidylinositol-3 kinase (PI3K) signaling pathway is a major regulator of B lymphocyte development and homeostasis. The Phosphoinositide-dependent protein kinase-1 (PDK1) is an important signaling hub of 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. Interestingly, PDK1 ablation results in an enhanced cell cycle entry and a block of 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 GSK3?/? and Foxo1. In summary, our results demonstrate that PDK1 is indispensable for B cell survival, proliferation, and growth regulation.