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 [Tesi di dottorato] (Unpublished)

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Item Type:	Tesi di dottorato
Lingua:	English
Title:	Control of PKA stability and signalling by RING ligase praja2
Creators:	Creators Email Lignitto, Luca lucagv@hotmail.it
Date:	29 November 2010
Number of Pages:	102
Institution:	Università degli Studi di Napoli Federico II
Department:	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:	nome email Avvedimento, Vittorio Enrico avvedim@unina.it
Tutor:	nome email Feliciello, Antonio feliciel@unina.it
Date:	29 November 2010
Number of Pages:	102
Uncontrolled Keywords:	AKAP, PKA, cAMP, ubiquitin, CREB, c-fos, LTP.
Settori scientifico-disciplinari del MIUR:	Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited:	10 Dec 2010 10:34
Last Modified:	30 Apr 2014 19:44
URI:	http://www.fedoa.unina.it/id/eprint/8129
DOI:	10.6092/UNINA/FEDOA/8129

Abstract

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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