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.

Control of PKA stability and signalling by the RING ligase praja2 / Lignitto, Luca; Carlucci, Annalisa; Sepe, Maria; Stefan, E; Cuomo, Ornella; Nisticò, R; Scorziello, Antonella; Savoia, Claudia; Garbi, Corrado; Annunziato, Lucio; Feliciello, Antonio. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 13:4(2011), pp. 412-422. [10.1038/ncb2209]

Control of PKA stability and signalling by the RING ligase praja2

LIGNITTO, LUCA;CARLUCCI, ANNALISA;SEPE, MARIA;CUOMO, ORNELLA;SCORZIELLO, ANTONELLA;SAVOIA, CLAUDIA;GARBI, CORRADO;ANNUNZIATO, LUCIO;FELICIELLO, ANTONIO
2011

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.
2011
Control of PKA stability and signalling by the RING ligase praja2 / Lignitto, Luca; Carlucci, Annalisa; Sepe, Maria; Stefan, E; Cuomo, Ornella; Nisticò, R; Scorziello, Antonella; Savoia, Claudia; Garbi, Corrado; Annunziato, Lucio; Feliciello, Antonio. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 13:4(2011), pp. 412-422. [10.1038/ncb2209]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/390704
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