title: Signaling diversity of PKA achieved via a Ca2+-cAMP-PKA oscillatory circuit.
abstract: 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), Ca(2+) and cyclic AMP (cAMP) oscillate in sync in insulin-secreting MIN6 beta 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 contribute to proper regulation of complex cellular functions in a context-dependent manner.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ni
authors.forename: Ambhighainath
authors.initials: A
authors.lastname: Ganesan
authors.forename: Nwe-Nwe
authors.initials: NN
authors.lastname: Aye-Han
authors.forename: Xinxin
authors.initials: X
authors.lastname: Gao
authors.forename: Michael D
authors.initials: MD
authors.lastname: Allen
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008853:Microscopy; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D002413:Cations, Divalent; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium