ArticleProceedings of the National Academy of Sciences of the United States of America2017
Mechanisms for restraining cAMP-dependent protein kinase revealed by subunit quantitation and cross-linking approaches.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 113 citations in OpenAlex.
- Functional divergence of protein kinase A regulatory subunit Iβ variants: the importance of N3A motifs in PKA regulation.The FEBS journal · 2026Article
- Review
- Beyond the mutations: spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis.Cellular & molecular biology letters · 2025Review
- Protein kinase A: a quirky prototype.The FEBS journal · 2025Article
- Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization.PLoS biology · 2025Article
- Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.Cell reports · 2025Article
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Phosphatases Control the Duration and Range of cAMP/PKA Microdomains.Function (Oxford, England) · 2025Article
- Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development.Circulation · 2024Article
- Translation regulation in response to stress.The FEBS journal · 2024Review
- Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac CaBMC biology · 2024Article
- Article
- A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species.Brain : a journal of neurology · 2024Article
- PKA regulation of neuronal function requires the dissociation of catalytic subunits from regulatory subunits.bioRxiv : the preprint server for biology · 2024Article
- Increased Protein Kinase A Activity Induces Fibrolamellar Hepatocellular Carcinoma Features Independent of DNAJB1.Cancer research · 2024Article
- Molecular determinants and signaling effects of PKA RIα phase separation.Molecular cell · 2024Article
- cAMP signaling: a remarkably regional affair.Trends in biochemical sciences · 2024Review
- The focal adhesion protein talin is a mechanically gated A-kinase anchoring protein.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Interaction networks explain holoenzyme allostery in Protein Kinase A.Kinases and phosphatases · 2023Article
- Neuronal ER-plasma membrane junctions couple excitation to CaNature communications · 2023Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Protein phosphorylation by cyclic AMP-dependent protein kinase (PKA) underlies key cellular processes, including sympathetic stimulation of heart cells, and potentiation of synaptic strength in neurons. Unrestrained PKA activity is pathological, and an enduring challenge is to understand how the activity of PKA catalytic subunits is directed in cells. We developed a light-activated cross-linking approach to monitor PKA subunit interactions with temporal precision in living cells. This enabled us to refute the recently proposed theory that PKA catalytic subunits remain tethered to regulatory subunits during cAMP elevation. Instead, we have identified other features of PKA signaling for reducing catalytic subunit diffusion and increasing recapture rate. Comprehensive quantitative immunoblotting of protein extracts from human embryonic kidney cells and rat organs reveals that regulatory subunits are always in large molar excess of catalytic subunits (average ∼17-fold). In the majority of organs tested, type II regulatory (RII) subunits were found to be the predominant PKA subunit. We also examined the architecture of PKA complexes containing RII subunits using cross-linking coupled to mass spectrometry. Quantitative comparison of cross-linking within a complex of RIIβ and Cβ, with or without the prototypical anchoring protein AKAP18α, revealed that the dimerization and docking domain of RIIβ is between its second cAMP binding domains. This architecture is compatible with anchored RII subunits directing the myristylated N terminus of catalytic subunits toward the membrane for release and recapture within the plane of the membrane.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.