Control of PKA stability and signalling by RING ligase praja2

Lignitto, Luca (2010) Control of PKA stability and signalling by RING ligase praja2. [Tesi di dottorato] (Inedito)

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Ligand-mediated activation of G-Protein Coupled Receptors (GPCRs) mobilises compartmentalised pulses of second messengers like cAMP. The main cellular effector of cAMP is Protein Kinase A (PKA) which is assembled as inactive holoenzyme consisting of two regulatory (R) and two catalytic (PKAc) subunits. cAMP binding to the R subunits dissociates the holoenzyme and releases the catalytic moiety, which phosphorylates a wide array of cellular proteins1. Re-association of the PKAc and R components terminates the signal. The rate of association and dissociation of R and PKAc subunits determines the intensity and the duration of the kinase activity, influencing complex biological phenotypes such as long term memory, differentiation and apoptosis2. Proteolysis of R subunits has been proposed as mechanism to sustain signalling downstream of PKAc3, although no enzyme targeting R subunits had been identified. Here we report that praja2, a RING E3 ligase widely expressed in mammalian cells, controls the stability of R subunits. Praja2 forms a stable complex with and is phosphorylated by PKA. Elevated cAMP levels promote Praja2-mediated ubiquitination and subsequent proteolysis of compartmentalised R subunits. Functional experiments in neuroblastoma cells and rat brains show that praja2 is required for efficient nuclear cAMP signalling and for PKA-mediated long-term potentiation (LTP). These findings indicate that praja2 regulates the total concentration of R subunits, thereby tuning the strength and duration of PKA signal output in response to the cAMP concentration.

Tipologia di documento:Tesi di dottorato
Parole chiave:AKAP, PKA, cAMP, ubiquitin, CREB, c-fos, LTP.
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/04 PATOLOGIA GENERALE
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
avvedimento, vittorio
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Stato del full text:Accessibile
Data:29 Novembre 2010
Numero di pagine:102
Istituzione:Università degli studi di Napoli Federico II
Dipartimento o Struttura:Biologia e patologia cellullare e molecolare "L. Califano"
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Patologia e fisiopatologia molecolare
Ciclo di dottorato:23
Numero di sistema:8129
Depositato il:10 Dicembre 2010 11:34
Ultima modifica:29 Agosto 2012 12:57

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