AKAP signaling: physiological and pathophysiological roles and opportunities for novel therapeutic concepts

A-kinase anchoring proteins (AKAPs) received their name based on their ability to bind protein kinase A (PKA). Now, AKAPs have grown to a diverse family of more than 50 proteins, coordinating molecules far beyond PKA and the PKA signaling pathway. AKAPs are scaffolding proteins spanning in size between 15 and several hundred kilodaltons and can directly engage in protein interactions with other signaling proteins, their upstream regulators, and their downstream effectors. AKAPs possess unique targeting domains directing them to defined cellular compartments to coordinate cellular signaling spatially and temporally. A few AKAPs possess their own catalytic activity. AKAPs are crucial in directing cAMP signaling locally and in mediating cross talk with other second messenger systems. This review introduces individual AKAPs and their physiological functions in their respective cellular compartments and illustrates how they organize local signal transduction. The crucial role of AKAPs in coordinating cAMP responses to extracellular cues and how they facilitate specific responses to each stimulus will be exemplified. Dysregulation of AKAPs is associated with or causes disease. We will examine the pathophysiological roles of AKAPs in inherited and noninherited noncommunicable diseases, such as cardiovascular diseases and cancer. Due to the lack of understanding of molecular mechanisms underlying most of these diseases, the available therapeutic approaches often only slow progression and cause side effects. This review will discuss the unique opportunities AKAPs provide to address the medical need for novel therapeutic concepts. Finally, gaps in our knowledge about AKAPs will be outlined, and future directions in AKAP research will be suggested.