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


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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: Control of PKA stability and signalling by RING ligase praja2
Data: 29 Novembre 2010
Numero di pagine: 102
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Biologia e patologia cellullare e molecolare "L. Califano"
Scuola di dottorato: Medicina molecolare
Dottorato: Patologia e fisiopatologia molecolare
Ciclo di dottorato: 23
Coordinatore del Corso di dottorato:
Avvedimento, Vittorio
Data: 29 Novembre 2010
Numero di pagine: 102
Parole chiave: AKAP, PKA, cAMP, ubiquitin, CREB, c-fos, LTP.
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il: 10 Dic 2010 10:34
Ultima modifica: 30 Apr 2014 19:44
DOI: 10.6092/UNINA/FEDOA/8129


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.

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