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

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 stimulat

SUBMITTER: O'Brien MT 

PROVIDER: S-EPMC5322397 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature