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

Article Details


Lignitto L, Carlucci A, Sepe M, Stefan E, Cuomo O, Nistico R, Scorziello A, Savoia C, Garbi C, Annunziato L, Feliciello A

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

Nat Cell Biol. 2011 Apr;13(4):412-22. doi: 10.1038/ncb2209. Epub 2011 Mar 20.

PubMed ID
21423175 [ View in PubMed

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.

DrugBank Data that Cites this Article

NameUniProt ID
cAMP-dependent protein kinase type II-alpha regulatory subunitP13861Details
cAMP-dependent protein kinase type I-alpha regulatory subunitP10644Details
cAMP-dependent protein kinase catalytic subunit alphaP17612Details
cAMP-dependent protein kinase catalytic subunit betaP22694Details
cAMP-dependent protein kinase type II-beta regulatory subunitP31323Details