Glycogen synthase kinase-3β (GSK3β) is a fascinating enzyme with an astoundingly diverse number of actions in intracellular signaling systems. GSK3β activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3β phosphorylates and thereby regulates the functions of many metabolic, signaling, and structural proteins. Notable among the signaling proteins regulated by GSK3β are the many transcription factors, including activator protein-1, cyclic AMP response element binding protein, heat shock factor-1, nuclear factor of activated T cells, Myc, β-catenin, CCAAT/enhancer binding protein, and NFκB. Lithium, the primary therapeutic agent for bipolar mood disorder, is a selective inhibitor of GSK3β. This raises the possibility that dysregulation of GSK3β and its inhibition by lithium may contribute to the disorder and its treatment, respectively. GSK3β has been linked to all of the primary abnormalities associated with Alzheimer's disease. These include interactions between GSK3β and components of the plaque-producing amyloid system, the participation of GSK3β in phosphorylating the microtubule-binding protein tau that may contribute to the formation of neurofibrillary tangles, and interactions of GSK3β with presenilin and other Alzheimer's disease-associated proteins. GSK3β also regulates cell survival, as it facilitates a variety of apoptotic mechanisms, and lithium provides protection from many insults. Thus, GSK3β has a central role regulating neuronal plasticity, gene expression, and cell survival, and may be a key component of certain psychiatric and neurodegenerative diseases.
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