The multifaceted roles of glycogen synthase kinase 3 beta 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 (stimu latory) phosphorylation, by protein complex formation, and by its intracell ular localization. GSK3 beta phosphorylates and thereby regulates the funct ions of many metabolic, signaling, and structural proteins. Notable among t he signaling proteins regulated by GSK3 beta are the many transcription fac tors, including activator protein-1, cyclic AMP response element binding pr otein, heat shock factor-1, nuclear factor of activated T cells, Myc, beta -catenin, CCAAT/enhancer binding protein, and NF kappaB. Lithium, the prima ry 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 abnormaliti es associated with Alzheimer's disease. These include interactions between GSK3 beta and components of the plaque-producing amyloid system, the partic ipation of GSK3 beta in phosphorylating the microtubule-binding protein tat that may contribute to the formation of neurofibrillary tangles, and inter actions of GSK3 beta with presenilin and other Alzheimer's disease-associat ed proteins. GSK3 beta also regulates cell survival, as it facilitates a va riety of apoptotic mechanisms, and lithium provides protection from many in sults. Thus, GSK3 beta has a central role regulating neuronal plasticity, g ene expression, and cell survival, and may be a key component of certain ps ychiatric and neurodegenerative diseases. (C) 2001 Elsevier Science Ltd. Al l rights reserved.