Control of PKA stability and signalling by the RING ligase praja2

Luca Lignitto, Annalisa Carlucci, Maria Sepe, Eduard Stefan, Ornella Cuomo, Robert Nisticó, Antonella Scorziello, Claudia Savoia, Corrado Garbi, Lucio Annunziato, Antonio Feliciello

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)412-424
Number of pages13
JournalNature Cell Biology
Volume13
Issue number4
DOIs
Publication statusPublished - Apr 2011

ASJC Scopus subject areas

  • Cell Biology

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    Lignitto, L., Carlucci, A., Sepe, M., Stefan, E., Cuomo, O., Nisticó, R., Scorziello, A., Savoia, C., Garbi, C., Annunziato, L., & Feliciello, A. (2011). Control of PKA stability and signalling by the RING ligase praja2. Nature Cell Biology, 13(4), 412-424. https://doi.org/10.1038/ncb2209