The multifaceted roles of glycogen synthase kinase 3β in cellular signaling

Glycogen synthase kinase-3 beta (GSK3 beta) is a fascinating enzyme with an astoundingly diverse number of actions in intracellular signaling systems. GSK3 beta activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3 beta phosphorylates and thereby regulates the functions of many metabolic, signaling, and structural proteins. Notable among the signaling proteins regulated by GSK3 beta 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, beta -catenin, CCAAT/enhancer binding protein, and NF kappaB. Lithium, the primary therapeutic agent for bipolar mood disorder, is a selective inhibitor of GSK3 beta. This raises the possibility that dysregulation of GSK3 beta and its inhibition by lithium may contribute to the disorder and its treatment, respectively. GSK3 beta has been linked to all of the primary abnormalities associated with Alzheimer's disease. These include interactions between GSK3 beta and components of the plaque-producing amyloid system, the participation of GSK3 beta in phosphorylating the microtubule-binding protein tat that may contribute to the formation of neurofibrillary tangles, and interactions of GSK3 beta with presenilin and other Alzheimer's disease-associated proteins. GSK3 beta also regulates cell survival, as it facilitates a variety of apoptotic mechanisms, and lithium provides protection from many insults. Thus, GSK3 beta has a central role regulating neuronal plasticity, gene expression, and cell survival, and may be a key component of certain psychiatric and neurodegenerative diseases. (C) 2001 Elsevier Science Ltd. All rights reserved.