title: Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4.
abstract: 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.
authors.affiliation: 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, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Nirula
authors.forename: Mary
authors.initials: M
authors.lastname: Ho
authors.forename: Hyewon
authors.initials: H
authors.lastname: Phee
authors.forename: Jeroen
authors.initials: J
authors.lastname: Roose
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism
chemical_list: D015847:Interleukin-4; D013912:Threonine; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases