scholarly journals AKAP79 enables calcineurin to directly suppress protein kinase A activity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Timothy W Church ◽  
Parul Tewatia ◽  
Saad Hannan ◽  
João Antunes ◽  
Olivia Eriksson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Hippocampal Neurons ◽  
Second Messengers ◽  
Capture Rate ◽  
Receptor Protein ◽  
Regulatory Subunits ◽  
Cellular Processes ◽  
Order Of Magnitude ◽  
Kinase A

Interplay between the second messengers cAMP and Ca2+ is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca2+-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD). AKAP79 supports signaling of this type by anchoring PKA and calcineurin in tandem. In this study, we discovered that AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory subunits by an order of magnitude. Fluorescent PKA activity reporter assays, supported by kinetic modeling, show how AKAP79-enhanced calcineurin activity enables suppression of PKA without altering cAMP levels by increasing PKA catalytic subunit capture rate. Experiments with hippocampal neurons indicate that this mechanism contributes towards LTD. This non-canonical mode of PKA regulation may underlie many other cellular processes.

scholarly journals AKAP79 enables calcineurin to directly suppress protein kinase A activity

2021 ◽  
Author(s):  
Timothy W. Church ◽  
Parul Tewatia ◽  
Saad Hannan ◽  
João Antunes ◽  
Olivia Eriksson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Hippocampal Neurons ◽  
Second Messengers ◽  
Capture Rate ◽  
Receptor Protein ◽  
Regulatory Subunits ◽  
Cellular Processes ◽  
Order Of Magnitude ◽  
Kinase A

Interplay between the second messengers cAMP and Ca2+ is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca2+-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD). AKAP79 supports signaling of this type by anchoring PKA and calcineurin in tandem. In this study, we discovered that AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory subunits by an order of magnitude. Fluorescent PKA activity reporter assays, supported by kinetic modeling, show how AKAP79-enhanced calcineurin activity enables suppression of PKA without altering cAMP levels by increasing PKA catalytic subunit capture rate. Experiments with hippocampal neurons indicate that this mechanism contributes towards LTD. This non-canonical mode of PKA regulation may underlie many other cellular processes.

Comparative Study of Active and Allosteric Interaction in Protein Kinases

2021 ◽  
Vol 8 (1) ◽  
pp. 23-31
Author(s):  
Jefrin Ahmed ◽  
Judith Mary Lamo ◽  
Baphilinia Jones Mylliemngap
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Kinases ◽  
Active Site ◽  
Cell Function ◽  
Binding Capacity ◽  
Second Messengers ◽  
Gene Families ◽  
Allosteric Site ◽  
Kinase A

Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. By adding phosphate groups to substrate proteins, they direct the activity, localization and overall function of many proteins, and serve to orchestrate the activity of almost all cellular processes. The main protein kinases consist of protein kinase A (PKA), protein kinase B (PKB), and protein kinase C (PKC) and are distinguished from each other by the different intracellular second messengers involved in their regulation and by the selective substrates they use. They all have a binding site for Mg2+-ATP (phosphate donor) and for substrate protein as well as various regulatory sites. We formulated to compare the binding capacity of protein kinases at the active site to allosteric sites. By comparing the active site and allosteric site of the protein kinases – A, B and C, using molecular docking it was found that in most of the cases the binding energy is high when an inhibitor binds to an active site as compared to the allosteric site. This comparison gave us an understanding of the interaction and inhibition of compounds to protein kinases in order to inhibit the activity of protein kinase A, B and C. It was concluded that for inhibiting the protein kinase function such as cell division and proliferation, binding of inhibitor to the allosteric site will be more effective.

scholarly journals Protein Kinase A (PKA)-Dependent Troponin-I Phosphorylation and PKA Regulatory Subunits Are Decreased in Human Dilated Cardiomyopathy

Circulation ◽  
1999 ◽  
Vol 99 (4) ◽  
pp. 505-510 ◽  
Author(s):  
Daniel R. Zakhary ◽  
Christine S. Moravec ◽  
Robert W. Stewart ◽  
Meredith Bond
Keyword(s):  
Protein Kinase ◽  
Dilated Cardiomyopathy ◽  
Protein Kinase A ◽  
Troponin I ◽  
Regulatory Subunits ◽  
Kinase A

scholarly journals Systematic identification of signal integration by protein kinase A

2015 ◽  
Vol 112 (14) ◽  
pp. 4501-4506 ◽  
Author(s):  
Marie Filteau ◽  
Guillaume Diss ◽  
Francisco Torres-Quiroz ◽  
Alexandre K. Dubé ◽  
Andrea Schraffl ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Interactions ◽  
Carbon Sources ◽  
Biological Processes ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Complex Formation ◽  
Growth And Aging ◽  
Kinase A

Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring protein–protein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA.

scholarly journals The Rapamycin-sensitive Phosphoproteome Reveals That TOR Controls Protein Kinase A Toward Some But Not All Substrates

2010 ◽  
Vol 21 (19) ◽  
pp. 3475-3486 ◽  
Author(s):  
Alexandre Soulard ◽  
Alessio Cremonesi ◽  
Suzette Moes ◽  
Frédéric Schütz ◽  
Paul Jenö ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Ribosome Biogenesis ◽  
Regulatory Subunit ◽  
Nutrient Metabolism ◽  
Cellular Processes ◽  
Targeted Analysis ◽  
Kinase A

Regulation of cell growth requires extensive coordination of several processes including transcription, ribosome biogenesis, translation, nutrient metabolism, and autophagy. In yeast, the protein kinases Target of Rapamycin (TOR) and protein kinase A (PKA) regulate these processes and are thereby the main activators of cell growth in response to nutrients. How TOR, PKA, and their corresponding signaling pathways are coordinated to control the same cellular processes is not understood. Quantitative analysis of the rapamycin-sensitive phosphoproteome combined with targeted analysis of PKA substrates suggests that TOR complex 1 (TORC1) activates PKA but only toward a subset of substrates. Furthermore, we show that TORC1 signaling impinges on BCY1, the negative regulatory subunit of PKA. Inhibition of TORC1 with rapamycin leads to BCY1 phosphorylation on several sites including T129. Phosphorylation of BCY1 T129 results in BCY1 activation and inhibition of PKA. TORC1 inhibits BCY1 T129 phosphorylation by phosphorylating and activating the S6K homolog SCH9 that in turn inhibits the MAP kinase MPK1. MPK1 phosphorylates BCY1 T129 directly. Thus, TORC1 activates PKA toward some substrates by preventing MPK1-mediated activation of BCY1.

Expression of protein kinase A regulatory subunits in benign and malignant human thyroid tissues: A systematic review

2016 ◽  
Vol 346 (1) ◽  
pp. 85-90 ◽  
Author(s):  
Alessandro Del Gobbo ◽  
Erika Peverelli ◽  
Donatella Treppiedi ◽  
Andrea Lania ◽  
Giovanna Mantovani ◽  
...  
Keyword(s):  
Systematic Review ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Human Thyroid ◽  
Regulatory Subunits ◽  
Kinase A
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