STK25 inhibits PKA signaling by phosphorylating PRKAR1A

Cell Rep. 2022 Aug 16;40(7):111203. doi: 10.1016/j.celrep.2022.111203.


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.

Keywords: CP: Cell biology; CP: Molecular biology; PRKAR1A; STK25; cardiomyocytes; induced pluripotent stem cell; kinase; protein kinase A.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / metabolism
  • Animals
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit* / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Myocytes, Cardiac / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases
  • Signal Transduction


  • Adrenergic Agents
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Intracellular Signaling Peptides and Proteins
  • PRKAR1A protein, human
  • Prkar1a protein, mouse
  • Stk25 protein, mouse
  • Protein Serine-Threonine Kinases
  • STK25 protein, human
  • Cyclic AMP-Dependent Protein Kinases