title: Control of PKA stability and signalling by the RING ligase praja2.
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.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Universitá Federico II, 80131 Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lignitto
authors.forename: Annalisa
authors.initials: A
authors.lastname: Carlucci
authors.forename: Maria
authors.initials: M
authors.lastname: Sepe
authors.forename: Eduard
authors.initials: E
authors.lastname: Stefan
authors.forename: Ornella
authors.initials: O
authors.lastname: Cuomo
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello
authors.forename: Claudia
authors.initials: C
authors.lastname: Savoia
authors.forename: Corrado
authors.initials: C
authors.lastname: Garbi
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
authors.forename: Antonio
authors.initials: A
authors.lastname: Feliciello
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004795:Enzyme Stability; D057809:HEK293 Cells; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; C588034:PJA2 protein, mouse; C094800:Pja2 protein, rat; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases