Glycogen synthase kinase (GSK)-3 beta has emerged as a key molecule that regulates neuronal apoptosis. To examine the molecular mechanism(s) through which GSK-3 beta regulates this process, we studied the subcellular localization of GSK-3 beta following exposure of the cells to well-characterized apoptotic stimuli. Here, we report that the induction of apoptosis by withdrawal of serum and potassium triggers dephosphorylation of GSK-3 beta at serine 9 and Subsequent translocation of these molecules into neuronal lipid raft microdomains. Inhibition of GSK-3P by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau. Consistent with the notion that the lipid raft domains may serve as a platform for the Cellular Signaling complexes, disruption of lipid rafts protected neurons from apoptosis induced by withdrawal of serum and potassium as well as by HIV-1 Tat. Our observations reveal novel interaction of GSK-3P and raft domains, and suggest that such interaction could contribute to neuronal apoptosis. (c) 2006 Elsevier Inc. All rights reserved.