Mechanisms of protein kinase A anchoring.
The second messenger cyclic adenosine monophosphate (cAMP), which is produced by adenylyl cyclases following stimulation of G-protein-coupled receptors, exerts its effect mainly through the cAMP-dependent serine/threonine protein kinase A (PKA). Due to the ubiquitous nature of the cAMP/PKA system, PKA signaling pathways underlie strict spatial and temporal control to achieve specificity. A-kinase anchoring proteins (AKAPs) bind to the regulatory subunit dimer of the tetrameric PKA holoenzyme and thereby target PKA to defined cellular compartments in the vicinity of its substrates. AKAPs promote the termination of cAMP signals by recruiting phosphodiesterases and protein phosphatases, and the integration of signaling pathways by binding additional signaling proteins. AKAPs are a heterogeneous family of proteins that only display similarity within their PKA-binding domains, amphipathic helixes docking into a hydrophobic groove formed by the PKA regulatory subunit dimer. This review summarizes the current state of information on compartmentalized cAMP/PKA signaling with a major focus on structural aspects, evolution, diversity, and (patho)physiological functions of AKAPs and intends to outline newly emerging directions of the field, such as the elucidation of AKAP mutations and alterations of AKAP expression in human diseases, and the validation of AKAP-dependent protein-protein interactions as new drug targets. In addition, alternative PKA anchoring mechanisms employed by noncanonical AKAPs and PKA catalytic subunit-interacting proteins are illustrated.
Skroblin
Philipp
P
Leibniz-Institute for Molecular Pharmacology, Berlin, Germany. skroblin@fmp-berlin.de
Grossmann
Solveig
S
Schäfer
Gesa
G
Rosenthal
Walter
W
Klussmann
Enno
E
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D004194:Disease; D006801:Humans; D015398:Signal Transduction
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases