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(Unpublished)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