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

Activation of G-protein-coupled receptors (GPCRs) mobilizes compartmentalized pulses of cyclic AMP. The main cellular effector of cAMP is protein kinase A which is assembled as an inactive holoenzyme consisting of two regulatory (R) and two catalytic subunits. cAMP binding to R subunits dissociates the holoenzyme and releases the catalytic moiety, which phosphorylates a wide array of cellular proteins. Reassociation of 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, 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 long-term memory. Thus, praja2 regulates the total concentration of R subunits, tuning the strength and duration of signal output in response to cAMP. © 2011 Macmillan Publishers Limited. All rights reserved

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