Control of PKA stability and signalling by the RING ligase praja2
Author: ["Luca Lignitto","Annalisa Carlucci","Maria Sepe","Eduard Stefan","Ornella Cuomo","Robert Nisticò","Antonella Scorziello","Claudia Savoia","Corrado Garbi","Lucio Annunziato","Antonio Feliciello"]
Publication: Nature Cell Biology
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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. The activity of protein kinase A (PKA) is regulated by association and dissociation of its regulatory (R) subunits. The E3 ubiquitin ligase praja2 is now shown to ubiquitylate and stimulate the degradation of the R subunits in response to elevated cAMP levels.
Cite this article
Lignitto, L., Carlucci, A., Sepe, M. et al. Control of PKA stability and signalling by the RING ligase praja2. Nat Cell Biol 13, 412–422 (2011). https://doi.org/10.1038/ncb2209
