Signaling diversity of PKA achieved via a Ca2+-cAMP-PKA oscillatory circuit. Nature Chemical Biology 7:34–40. doi: 10.1038/ nchembio.478

Many protein kinases are key nodal signaling molecules that regulate a wide range of cellular functions. These functions may require complex spatiotemporal regulation of kinase activities. Here, we show that Protein Kinase A (PKA), Ca2+ and cAMP oscillate in sync in insulin-secreting MIN6 β cells, forming a highly integrated oscillatory circuit. We found that PKA activity was essential for this oscillatory circuit, and was capable of not only initiating the signaling oscillations but also modulating their frequency, thereby diversifying the spatiotemporal control of downstream signaling. Our findings suggest that exquisite temporal control of kinase activity, mediated via signaling circuits resulting from cross-regulation of signaling pathways, can encode diverse inputs into temporal parameters such as oscillation frequency, which in turn contributes to proper regulation of complex cellular functions in a context-dependent manner. Protein kinases serve as major information transducers in cells and are responsible for regulating diverse cellular functions1,2. However, the molecular mechanisms underlying this signaling diversity are not well understood, particularly with regard to the role of the spatiotemporal regulation of kinases. Although important progress has been made i