Dataset Information

Ca2+/Calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation.

ABSTRACT: Ca(2+)/calmodulin-dependent protein kinase kinase ? (CaMKK?) is a serine/threonine-directed kinase that is activated following increases in intracellular Ca(2+). CaMKK? activates Ca(2+)/calmodulin-dependent protein kinase I, Ca(2+)/calmodulin-dependent protein kinase IV, and the AMP-dependent protein kinase in a number of physiological pathways, including learning and memory formation, neuronal differentiation, and regulation of energy balance. Here, we report the novel regulation of CaMKK? activity by multisite phosphorylation. We identify three phosphorylation sites in the N terminus of CaMKK?, which regulate its Ca(2+)/calmodulin-independent autonomous activity. We then identify the kinases responsible for these phosphorylations as cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3). In addition to regulation of autonomous activity, we find that phosphorylation of CaMKK? regulates its half-life. We find that cellular levels of CaMKK? correlate with CDK5 activity and are regulated developmentally in neurons. Finally, we demonstrate that appropriate phosphorylation of CaMKK? is critical for its role in neurite development. These results reveal a novel regulatory mechanism for CaMKK?-dependent signaling cascades.

SUBMITTER: Green MF

PROVIDER: S-EPMC3151052 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Ca2+/Calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation.

Green Michelle F MF Scott John W JW Steel Rohan R Oakhill Jonathan S JS Kemp Bruce E BE Means Anthony R AR

The Journal of biological chemistry 20110613 32

Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) is a serine/threonine-directed kinase that is activated following increases in intracellular Ca(2+). CaMKKβ activates Ca(2+)/calmodulin-dependent protein kinase I, Ca(2+)/calmodulin-dependent protein kinase IV, and the AMP-dependent protein kinase in a number of physiological pathways, including learning and memory formation, neuronal differentiation, and regulation of energy balance. Here, we report the novel regulation of CaMKKβ acti ...[more]

PMID: 21669867

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Project description:During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.

Dataset Information

Ca2+/Calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation.

Publications

Ca2+/Calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation.

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