The biological functions of A-kinase anchor proteins

cAMP-dependent protein kinase is targeted to discrete subcellular locations by a family of specific anchor proteins (A-kinase anchor proteins, AKAPs). Localization recruits protein kinase A (PKA) holoenzyme close to its subst rate/effector proteins, directing and amplifying the biological effects of cAMP signaling. AKAPs include two conserved structural modules: (i) a targeting domain that serves as a scaffold and membrane anchor; and (ii) a tethering domain that interacts with PKA regulatory subunits. Alternative splicing can shuffle t argeting and tethering domains to generate a variety of AKAPs with differen t targeting specificity. Although AKAPs have been identified on the basis o f their interaction with PKA, they also bind other signaling molecules, mai nly phosphatases and kinases, that regulate AKAP targeting and activate oth er signal transduction pathways. We suggest that AKAP forms a "transduceosome" by acting as an autonomous mu ltivalent scaffold that assembles and integrates signals derived from multi ple pathways. The transduceosome amplifies cAMP and other signals locally a nd, by stabilizing and reducing the basal activity of PKA, it also exerts l ong-distance effects. The AKAP transduceosome thus optimizes the amplitude and the signal/noise ratio of cAMP-PKA stimuli travelling from the membrane to the nucleus and other subcellular compartments. (C) 2001 Academic Press .