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Control of PKA stability and signalling by the RING ligase praja2.

Authors: Lignitto, L  Carlucci, A  Sepe, M  Stefan, E  Cuomo, O  Nistico, R  Scorziello, A  Savoia, C  Garbi, C  Annunziato, L  Feliciello, A 
Citation: Lignitto L, etal., Nat Cell Biol. 2011 Apr;13(4):412-22. doi: 10.1038/ncb2209. Epub 2011 Mar 20.
Pubmed: (View Article at PubMed) PMID:21423175
DOI: Full-text: DOI:10.1038/ncb2209

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.

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CRRD Object Information
CRRD ID: 8554183
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE



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