ArticleThe Journal of biological chemistry2010
cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 96 citations in OpenAlex.
- Protein phosphatase 2A is regulated by protein kinase Cα (PKCα)-dependent phosphorylation of its targeting subunit B56α at Ser41.The Journal of biological chemistry · 2014Trial
- AKAP6β-a conductor in the orchestra of pathological cardiomyocyte gene transcription.Molecular pharmacology · 2026Review
- Lipopeptides modulate lipid metabolism and immune performance in largemouth bass (Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2026Article
- The adeno-associated virus Rep proteins target PP4:SMEK1 by preventing substrate recruitment.PLoS pathogens · 2026Article
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Targeting Odorant Receptors in Adipose Tissue with Food-Derived Odorants: A Novel Approach to Obesity Treatment.Foods (Basel, Switzerland) · 2024Review
- Recent advances in serum response factor posttranslational modifications and their therapeutic potential in cardiovascular and neurological diseases.Vascular pharmacology · 2024Review
- Protein phosphatase 2A anchoring disruptor gene therapy for familial dilated cardiomyopathy.Molecular therapy. Methods & clinical development · 2024Article
- B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Loss of protein phosphatase 2A regulatory subunitFrontiers in cardiovascular medicine · 2024Article
- Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy.Gene therapy · 2023Article
- Disease mutations and phosphorylation alter the allosteric pathways involved in autoinhibition of protein phosphatase 2A.The Journal of chemical physics · 2023Article
- Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme.bioRxiv : the preprint server for biology · 2023Article
- Regulation of cardiac function by cAMP nanodomains.Bioscience reports · 2023Review
- Hypercontractile cardiac phenotype in mice overexpressing the regulatory subunit PR72 of protein phosphatase 2A.Frontiers in cardiovascular medicine · 2023Article
- Renal ATCirculation research · 2022Article
- Mobile Anchors.Function (Oxford, England) · 2022Article
- Regulation of Cardiac PKA Signaling by cAMP and Oxidants.Antioxidants (Basel, Switzerland) · 2021Review
- Subcellular Organization of the cAMP Signaling Pathway.Pharmacological reviews · 2021Review
- Signalosome-Regulated Serum Response Factor Phosphorylation Determining Myocyte Growth in Width Versus Length as a Therapeutic Target for Heart Failure.Circulation · 2020Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 6 institutions in 2 countries.
Funding
Abstract
The concentration of the second messenger cAMP is tightly controlled in cells by the activity of phosphodiesterases. We have previously described how the protein kinase A-anchoring protein mAKAP serves as a scaffold for the cAMP-dependent protein kinase PKA and the cAMP-specific phosphodiesterase PDE4D3 in cardiac myocytes. PKA and PDE4D3 constitute a negative feedback loop whereby PKA-catalyzed phosphorylation and activation of PDE4D3 attenuate local cAMP levels. We now show that protein phosphatase 2A (PP2A) associated with mAKAP complexes is responsible for reversing the activation of PDE4D3 by catalyzing the dephosphorylation of PDE4D3 serine residue 54. Mapping studies reveal that a C-terminal mAKAP domain (residues 2085-2319) binds PP2A. Binding to mAKAP is required for PP2A function, such that deletion of the C-terminal domain enhances both base-line and forskolin-stimulated PDE4D3 activity. Interestingly, PP2A holoenzyme associated with mAKAP complexes in the heart contains the PP2A targeting subunit B56delta. Like PDE4D3, B56delta is a PKA substrate, and PKA phosphorylation of mAKAP-bound B56delta enhances phosphatase activity 2-fold in the complex. Accordingly, expression of a B56delta mutant that cannot be phosphorylated by PKA results in increased PDE4D3 phosphorylation. Taken together, our findings demonstrate that PP2A associated with mAKAP complexes promotes PDE4D3 dephosphorylation, serving both to inhibit PDE4D3 in unstimulated cells and also to mediate a cAMP-induced positive feedback loop following adenylyl cyclase activation and B56delta phosphorylation. In general, PKA.PP2A.mAKAP complexes exemplify how protein kinases and phosphatases may participate in molecular signaling complexes to dynamically regulate localized intracellular signaling.
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