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    Impact of Genetic Variation on Human CaMKK2 Regulation by Ca2+-Calmodulin and Multisite Phosphorylation

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    Author
    O'Brien, MT; Oakhill, JS; Ling, NXY; Langendorf, CG; Hoque, A; Dite, TA; Means, AR; Kemp, BE; Scott, JW
    Date
    2017-02-23
    Source Title
    Scientific Reports
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Kemp, Bruce; Oakhill, Jonathan; Dite, Toby; Hoque, Md Ashfaqul
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    O'Brien, M. T., Oakhill, J. S., Ling, N. X. Y., Langendorf, C. G., Hoque, A., Dite, T. A., Means, A. R., Kemp, B. E. & Scott, J. W. (2017). Impact of Genetic Variation on Human CaMKK2 Regulation by Ca2+-Calmodulin and Multisite Phosphorylation. SCIENTIFIC REPORTS, 7 (1), https://doi.org/10.1038/srep43264.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258188
    DOI
    10.1038/srep43264
    Abstract
    The Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and whole-body energy metabolism. Elevated CaMKK2 activity is strongly associated with prostate and hepatic cancers, whereas reduced CaMKK2 activity has been linked to schizophrenia and bipolar disease in humans. Here we report the functional effects of nine rare-variant point mutations that were detected in large-scale human genetic studies and cancer tissues, all of which occur close to two regulatory phosphorylation sites and the catalytic site on human CaMKK2. Four mutations (G87R, R139W, R142W and E268K) cause a marked decrease in Ca2+-independent autonomous activity, however S137L and P138S mutants displayed increased autonomous and Ca2+-CaM stimulated activities. Furthermore, the G87R mutant is defective in Thr85-autophosphorylation dependent autonomous activity, whereas the A329T mutation rendered CaMKK2 virtually insensitive to Ca2+-CaM stimulation. The G87R and R139W mutants behave as dominant-negative inhibitors of CaMKK2 signaling in cells as they block phosphorylation of the downstream substrate AMP-activated protein kinase (AMPK) in response to ionomycin. Our study provides insight into functionally disruptive, rare-variant mutations in human CaMKK2, which have the potential to influence risk and burden of disease associated with aberrant CaMKK2 activity in human populations carrying these variants.

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