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.

Lignitto, L., Carlucci, A., Sepe, M., Stefan, E., Cuomo, O., Nistico', R.g., et al. (2011). Control of PKA stability and signalling by the RING ligase praja2. NATURE CELL BIOLOGY, 13(4), 412-424 [10.1038/ncb2209].

Control of PKA stability and signalling by the RING ligase praja2

NISTICO', ROBERT GIOVANNI;
2011-01-01

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
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
A Kinase Anchor Proteins; Animals; Cell Line, Tumor; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; DNA-Binding Proteins; Enzyme Activation; HEK293 Cells; Humans; Long-Term Potentiation; Mice; Neuroblastoma; Neurons; Protein Subunits; Proto-Oncogene Proteins c-fos; Rats; Recombinant Fusion Proteins; Signal Transduction; Two-Hybrid System Techniques; Ubiquitin-Protein Ligases; Enzyme Stability
Lignitto, L., Carlucci, A., Sepe, M., Stefan, E., Cuomo, O., Nistico', R.g., et al. (2011). Control of PKA stability and signalling by the RING ligase praja2. NATURE CELL BIOLOGY, 13(4), 412-424 [10.1038/ncb2209].
Lignitto, L; Carlucci, A; Sepe, M; Stefan, E; Cuomo, O; Nistico', Rg; Scorziello, A; Savoia, C; Garbi, C; Annunziato, L; Feliciello, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/133176
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