STK25 inhibits PKA signaling by phosphorylating PRKAR1A.
STK25 inhibits PKA signaling by phosphorylating PRKAR1A.
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DOI：
10.1016/j.celrep.2022.111203
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发表时间：
2022-08-16
期刊：
影响因子：
8.8
通讯作者：
Fine, Barry
中科院分区：
文献类型：
--
作者：
Zhang, Xiaokan;Wang, Bryan Z.;Kim, Michael;Nash, Trevor R.;Liu, Bohao;Rao, Jenny;Lock, Roberta;Tamargo, Manuel;Soni, Rajesh Kumar;Belov, John;Li, Eric;Vunjak-Novakovic, Gordana;Fine, Barry
In 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 that 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 utilize human induced pluripotent stem cell cardiomyocytes (iPSC-CMs) to identify STK25 as a kinase of the type Iα regulatory subunit PRKAR1A. Phosphorylation of PRKAR1A leads to inhibition of PKA kinase activity and increased binding to the catalytic subunit in the presence of cAMP. Stk25 knockout in mice diminishes Prkar1a phosphorylation, increases Pka activity, and augments contractile response to beta-adrenergic stimulation. Together, these data support STK25 as a negative regulator of PKA signaling through phosphorylation of PRKAR1A. Zhang et al. use both in vitro and in vivo cardiomyocyte models to demonstrate that STK25 phosphorylates the type Iα regulatory subunit of PKA, PRKAR1A. This leads to increased inhibition of PKA signaling and attenuation of cAMP-mediated increases in cardiac contractile function.
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