Ca 2 /calmodulin-dependent protein kinase kinase β is regulated by multisite phosphorylation

Abstract

Ca 2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is a serine/threonine-directed kinase that is activated following increases in intracellular Ca2+. CaMKKβ activates Ca2+/calmodulin-dependent protein kinase I, Ca2+/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 activity by multisite phosphorylation. We identify three phosphorylation sites in the N terminus of CaMKKβ, which regulate its Ca2+/calmodulin-independent autonomous activity. We then identify the kinases respon..