Abstract
A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling
Highlights
protein kinase (PKA) exists in the cytoplasm as an inactivated tetramer holoenzyme composed of dimer catalytic subunits and dimer regulatory subunits, which dissociate upon elevation of cAMP (6 –10)
We provide evidence that in minimal AKIP1-expressing cell lines, elevation of cAMP decreased p65-PKA binding and p65 phosphorylation at Ser-276, which eventually leads to down-regulation of the NF-B-dependent transcription
We found that AKIP1 could regulate the mode of PKA signaling on NF-B cascade based on its expression level
Summary
PKA exists in the cytoplasm as an inactivated tetramer holoenzyme composed of dimer catalytic subunits and dimer regulatory subunits, which dissociate upon elevation of cAMP (6 –10). The p65/p50 heterodimer complex is liberated, and the catalytic center of PKAc is exposed, enabling activated PKAc to phosphorylate p65 at Ser-276 [14, 15] This PKA-dependent phosphorylation of p65 facilitates the recruitment of transcription coactivator CBP and DNA binding activity of p65; activation of PKA augments NF-B-dependent gene expression, and PKAc signaling is considered to up-regulate NF-B activation (14 –17). With regard to the role of PKAc in NF-B signaling, some claimed that cAMP-dependent PKA activation down-regulated NF-B-dependent transcription by changing its DNA binding ability [18, 19], modifying the transactivation domain of p65 [20], or blocking the degradation of IB proteins [21, 22]. In breast cancer cell lines MDA-MB231 and MCF7 with high AKIP1 expression, the PKA-activating agents increased p65-PKA binding and its phosphorylation and up-regulated the NF-B-dependent transcription, in anti-apoptotic genes.
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