Control of PKA stability and signalling by the RING ligase praja2

Nat Cell Biol. 2011 Apr;13(4):412-22. doi: 10.1038/ncb2209. Epub 2011 Mar 20.

Abstract

Activation of G-protein-coupled receptors (GPCRs) mobilizes compartmentalized pulses of cyclic AMP. The main cellular effector of cAMP is protein kinase A (PKA), which is assembled as an inactive holoenzyme consisting of two regulatory (R) and two catalytic (PKAc) subunits. cAMP binding to R subunits dissociates the holoenzyme and releases the catalytic moiety, which phosphorylates a wide array of cellular proteins. Reassociation of PKAc and R components terminates the signal. Here we report that the RING ligase praja2 controls the stability of mammalian R subunits. Praja2 forms a stable complex with, and is phosphorylated by, PKA. Rising cAMP levels promote praja2-mediated ubiquitylation and subsequent proteolysis of compartmentalized R subunits, leading to sustained substrate phosphorylation by the activated kinase. Praja2 is required for efficient nuclear cAMP signalling and for PKA-mediated long-term memory. Thus, praja2 regulates the total concentration of R subunits, tuning the strength and duration of PKA signal output in response to cAMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism
  • Animals
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • Enzyme Stability*
  • HEK293 Cells
  • Humans
  • Long-Term Potentiation / physiology
  • Mice
  • Neuroblastoma
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology*
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • A Kinase Anchor Proteins
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Protein Subunits
  • Proto-Oncogene Proteins c-fos
  • Recombinant Fusion Proteins
  • Cyclic AMP
  • PJA2 protein, mouse
  • Pja2 protein, rat
  • Ubiquitin-Protein Ligases
  • Cyclic AMP-Dependent Protein Kinases