ArticleThe Journal of biological chemistry2014
Scaffold state switching amplifies, accelerates, and insulates protein kinase C signaling.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- Single-cell dynamics reveal a stress-induced decision between hypertrophy and apoptosis in neonatal rat cardiomyocytes.Journal of molecular and cellular cardiology plus · 2025Article
- The regulatory function of mixed lineage kinase 3 in tumor and host immunity.Pharmacology & therapeutics · 2021Review
- Sex Difference of Ribosome in Stroke-Induced Peripheral Immunosuppression by Integrated Bioinformatics Analysis.BioMed research international · 2020Article
- Effective concentrations enforced by intrinsically disordered linkers are governed by polymer physics.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Switching of INCENP paralogs controls transitions in mitotic chromosomal passenger complex functions.Cell cycle (Georgetown, Tex.) · 2019Article
- Genetically Encoded Fluorescent Biosensors Illuminate the Spatiotemporal Regulation of Signaling Networks.Chemical reviews · 2018Review
- Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Predictive model identifies key network regulators of cardiomyocyte mechano-signaling.PLoS computational biology · 2017Article
- Building collagen IV smart scaffolds on the outside of cells.Protein science : a publication of the Protein Society · 2017Review
- Illuminating the Cell's Biochemical Activity Architecture.Biochemistry · 2017Review
- Optical sensors to gain mechanistic insights into signaling assemblies.Current opinion in structural biology · 2016Review
- Computational modeling of cardiac fibroblasts and fibrosis.Journal of molecular and cellular cardiology · 2016Review
- Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates.Cell metabolism · 2015Article
- Common mechanisms of Alzheimer's disease and ischemic stroke: the role of protein kinase C in the progression of age-related neurodegeneration.Journal of Alzheimer's disease : JAD · 2015Review
- Tuning the signalling output of protein kinase C.Biochemical Society transactions · 2014Review
- Modeling CaMKII in cardiac physiology: from molecule to tissue.Frontiers in pharmacology · 2014Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Scaffold proteins localize two or more signaling enzymes in close proximity to their downstream effectors. A-kinase-anchoring proteins (AKAPs) are a canonical family of scaffold proteins known to bind protein kinase A (PKA) and other enzymes. Several AKAPs have been shown to accelerate, amplify, and specify signal transduction to dynamically regulate numerous cellular processes. However, there is little theory available to mechanistically explain how signaling on protein scaffolds differs from solution biochemistry. In our present study, we propose a novel kinetic mechanism for enzymatic reactions on protein scaffolds to explain these phenomena, wherein the enzyme-substrate-scaffold complex undergoes stochastic state switching to reach an active state. This model predicted anchored enzymatic reactions to be accelerated, amplified, and insulated from inhibition compared with those occurring in solution. We exploited a direct interaction between protein kinase C (PKC) and AKAP7α as a model to validate these predictions experimentally. Using a genetically encoded PKC activity reporter, we found that both the strength and speed of substrate phosphorylation were enhanced by AKAP7α. PKC tethered to AKAP7α was less susceptible to inhibition from the ATP-competitive inhibitor Gö6976 and the substrate-competitive inhibitor PKC 20-28, but not the activation-competitive inhibitor calphostin C. Model predictions and experimental validation demonstrated that insulation is a general property of scaffold tethering. Sensitivity analysis indicated that these findings may be applicable to many other scaffolds as well. Collectively, our findings provide theoretical and experimental evidence that scaffold proteins can amplify, accelerate, and insulate signal transduction.
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