The Journal of Experimental Medicine
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Published online 19 June 2006 doi:10.1084/jem.20051715
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 7, 1733-1744
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ARTICLE

 Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4

Ajay Nirula, Mary Ho, Hyewon Phee, Jeroen Roose, and Arthur Weiss

Department of Medicine, The Rosalind Russell Medical Research Center for Arthritis and the Howard Hughes Medical Institute, University of California at San Francisco, CA 94143

CORRESPONDENCE Arthur Weiss: aweiss{at}medicine.ucsf.edu

CD28 plays a critical role in T cell immune responses. Although the kinase Akt has been shown to act downstream of CD28 in T helper (Th)1 cytokine induction, it does not induce Th2 cytokines such as interleukin 4 (IL-4). We recently reported that phosphoinositide-dependent kinase 1 (PDK1) partially corrects the defect in IL-4 production present in CD28-deficient T cells, suggesting that PDK1 regulates IL-4 independently of Akt. We now describe a signaling pathway in which PDK1 targets IL-4 in the murine Th2 cell line D10. PDK1-mediated activation of this pathway is dependent on protein kinase A (PKA) and the nuclear factor of activated T cells (NFAT) P1 transcriptional element in the IL-4 promoter. PDK1 localizes to the immune synapse in a phosphatidylinositol 3-kinase–dependent manner, partially colocalizes with PKA at the synapse, and physically interacts with PKA. In RNA interference knockdown experiments, PDK1 is necessary for phosphorylation of PKA in T cells, as well as for activation of the IL-4 NFAT P1 element by the T cell receptor (TCR) and CD28. Phosphorylation of the critical PKA threonine residue is stimulated by engagement of TCR/CD28 via a PDK1-dependent mechanism. These findings together define a pathway linking the kinases PDK1 and PKA in the induction of the Th2 cytokine IL-4.

Abbreviations used: AKAP, A-kinase anchoring protein; CRE, cAMP-responsive element; DN, dominant negative; KH, kinase hyperactive; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PIF, PDK-interacting fragment; PKA, protein kinase A; PKAc, PKA catalytic subunit; RNAi, RNA interference; siRNA, small interfering RNA.


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