The many faces of compartmentalized PKA signalosomes

Cellular signal transmission requires the dynamic formation of spatiotemporally controlled molecular interactions. At the cell surface information is received by receptor complexes and relayed through intracellular signaling platforms which organize the actions of functionally interacting signaling enzymes and substrates. The list of hormone or neurotransmitter pathways that utilize the ubiquitous cAMP-sensing protein kinase A (PKA) system is expansive. This requires that the specificity, duration, and intensity of PKA responses are spatially and temporally restricted. Hereby, scaffolding proteins take the center stage for ensuring proper signal transmission. They unite second messenger sensors, activators, effectors, and kinase substrates within cellular micro-domains to precisely control and route signal propagation. A-kinase anchoring proteins (AKAPs) organize such subcellular signalosomes by tethering the PKA holoenzyme to distinct cell compartments. AKAPs differ in their modular organization showing pathway specific arrangements of interaction motifs or domains. This enables the cell- and compartment- guided assembly of signalosomes with unique enzyme composition and function. The AKAP-mediated clustering of cAMP and other second messenger sensing and interacting signaling components along with functional successive enzymes facilitates the rapid and precise dissemination of incoming signals. This review article delineates examples for different means of PKA regulation and for snapshots of compartmentalized PKA signalosomes.