STK25 inhibits PKA signaling by phosphorylating PRKAR1A
| Autor: | Xiaokan Zhang, Bryan Z. Wang, Michael Kim, Trevor R. Nash, Bohao Liu, Jenny Rao, Roberta Lock, Manuel Tamargo, Rajesh Kumar Soni, John Belov, Eric Li, Gordana Vunjak-Novakovic, Barry Fine |
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| Rok vydání: | 2022 |
| Předmět: |
Mice
Adrenergic Agents Cyclic AMP-Dependent Protein Kinase RIalpha Subunit Induced Pluripotent Stem Cells Intracellular Signaling Peptides and Proteins Animals Humans Myocytes Cardiac Phosphorylation Protein Serine-Threonine Kinases Cyclic AMP-Dependent Protein Kinases General Biochemistry Genetics and Molecular Biology Signal Transduction |
| Zdroj: | Cell Reports. 40:111203 |
| ISSN: | 2211-1247 |
| Popis: | SummaryIn the heart, Protein Kinase A (PKA) is critical for activating calcium handling and sarcomeric proteins in response to beta adrenergic stimulation leading to increased myocardial contractility and performance. The catalytic activity of PKA is tightly regulated by regulatory subunits which inhibit the catalytic subunit until released by cAMP binding. Phosphorylation of Type II regulatory subunits promotes PKA activation, however the role of phosphorylation in Type I regulatory subunits remain uncertain. Here we utilized human induced pluripotent stem cell cardiomyocytes (iPSC-CM) to identify STK25 as a kinase of the Type Ia regulatory subunit PRKAR1A. Phosphorylation of PRKAR1A led to inhibition of PKA kinase activity and increased binding to the catalytic subunit in the presence of cAMP. Stk25 knockout in mice diminished Prkar1a phosphorylation, increased Pka activity and augmented contractile response to beta adrenergic stimulation. Together, these data support STK25 as a negative regulator of PKA signaling through phosphorylation of PRKAR1A. |
| Databáze: | OpenAIRE |
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