The Transcriptional Activity of NF-κB Is Regulated by the IκB-Associated PKAc Subunit through a Cyclic AMP–Independent Mechanism

Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Cell (Impact Factor: 32.24). 06/1997; 89(3):413-24. DOI: 10.1016/S0092-8674(00)80222-6
Source: PubMed

ABSTRACT Stimulation of cells with inducers of NF-kappaB such as LPS and IL-1 leads to the degradation of IkappaB-alpha and IkappaB-beta proteins and translocation of NF-kappaB to the nucleus. We now demonstrate that, besides the physical partitioning of inactive NF-kappaB to the cytosol, the transcriptional activity of NF-kappaB is regulated through phosphorylation of NF-kappaB p65 by protein kinase A (PKA). The catalytic subunit of PKA (PKAc) is maintained in an inactive state through association with IkappaB-alpha or IkappaB-beta in an NF-kappaB-IkappaB-PKAc complex. Signals that cause the degradation of IkappaB result in activation of PKAc in a cAMP-independent manner and the subsequent phosphorylation of p65. Therefore, this pathway represents a novel mechanism for the cAMP-independent activation of PKA and the regulation of NF-kappaB activity.

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Available from: Hediye Erdjument-Bromage, Apr 29, 2015
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    • "It appears that NOD1 engages both ERK and PKA pathways to regulate lipolysis, since simultaneously inhibiting both of these pathways completely prevented any increase in glycerol release from adipocytes. ERK is a well-known factor in the NF-κB pathway and others have shown connections between PKA and NF-κB signaling events, even in response to inflammatory triggers such as TNFα [38], [39]. Intriguingly, PKA subunits can be found in an NF-κB and IκB complex. "
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    PLoS ONE 05/2014; 9(5):e97675. DOI:10.1371/journal.pone.0097675 · 3.23 Impact Factor
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    • "The Ser276 residue of RelA can be phosphorylated, has been shown to be targeted by the catalytic subunit of protein kinase A (PKA), mitogen- and stress-activated protein kinase-1 (MSK1), and Pim1 kinase (42–45). The importance of this phosphorylated serine was shown to be threefold: it moderately enhanced DNA-binding activity of RelA; it caused a conformational shift that allowed CBP/p300 binding in place of the latent interaction of RelA with HDAC complexes; RelA deficient cells reconstituted with S276A mutants were severely impaired in NF-κB dependent gene expression (32, 45–48) (Figure 2). Most convincingly, the absolute necessity of this phosphorylation event was demonstrated by the generation of a knock-in mouse containing an alanine substitution at RelA S276 residue. "
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    Frontiers in Immunology 02/2014; 5:71. DOI:10.3389/fimmu.2014.00071
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    • "Recent data have shown that the elevation of intracellular cAMP levels inhibits the transcriptional activity of NF-jB [47] [48]. Possible mechanisms underlying the role of cAMP in regulating NF-jB activity include the ability of cAMP to manage IKK activity and IkB degradation as well as the ability to change the composition of NF-jB dimmers and thereby block transcription [48]. "
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