HIV-mediated neuronal damage Inhibits NF-κB [55–57]. International Journal of Cell Biology System or stimulus Mechanism C(2) Ceramide-associated damage LPS-mediated endotoxic shock Immune system Neurodegenerative disease-related toxicity and oxidative stress ER stress Hypoxia/ischemia Table 1: Conditions where GSK-3β facilitates apoptosis. Inhibits the phosphorylation of AKT and ERK pathways and through the dephosphorylation of GSK-3β [51]. GSK-3β inhibitors have been shown to inhibit apoptosis through inhibiting dephosphorylation of AKT and GSK-3β [52]. While speciﬁc apoptotic studies have not been performed, LPS has been shown to stabilize apoptotic signal-regulating kinase-1 (ASK-1), a serine-threonine kinase associated with stress-induced apoptosis [53]. Regulates in apoptosis of activated T-Cells [54]. Neuronal or oligodendrocyte injury or toxicity (including prion peptide) is associated with increased activity of GSK-3β[51, 58–64]. Negative regulators of GSK-3β are associated with increased survival factors [51, 58–64] and neuroprotection [9, 38]. ER stress can lead to dephosphorylation of pGSK-3β(S9), leading to stress-induced apoptosis through activated caspase-3 [12–14, 26, 28]. Activates mitochondrial death pathway [35, 65–68]. 3 ZAK1 Fyn Ca++ AKT PKA/PKCp90Rsk Ser-9 Active Tyr-216 P GSK-3β Ser-9 Tyr-216 GSK-3β Ser-9 Inactive P GSK-3β Tyr-216 P β-catenin P Cell cycle WNT signaling pathway Proteasomal degradation Cyclin D1 β-catenin β-catenin β-catenin β-catenin β-catenin Accumulation Figure 2: Regulation of GSK-3β. GSK-3β is a multifunctional kinase that has a role in various signaling pathways that regulate cell fate. ZAK1 or Fyn can phosphorylate Tyr-216 which increases the GSK-3β activity. GSK-3β can phosphorylate downstream targets like β-catenin and degrade it through the ubiquitin-proteasome system. Akt and PKC on the other hand can attenuate GSK-3β enzymatic activity by phosphorylating Ser-9. Inhibition of GSK-3β activity therefore leads to stabilization and accumulation of β-catenin in the cytosol, which is shuttled into the nucleus where it functions to regulate gene expression. GSK-3β is also involved in cell cycle regulation through the phosphorylation of cyclin D1, which results in the rapid proteolytic turnover of cyclin D1 protein. is multifaceted. In the classical model, N-terminal phospho- rylation of p53 at Ser-15 (mouse Ser-18) and Ser-20 (mouse Ser-23) inhibits the interaction with MDM2 and thereby prevents MDM2-mediated ubiquitination and the resulting proteasomal degradation of p53 [44] (Figure 3). Stabilized p53 then enters a complex regulatory network to induce DNA binding and transcriptional activation of p53 target genes, in part through the recruitment of coactivators and corepressors. This determines the speciﬁc cellular response, which can include survival, growth arrest, DNA repair, or apoptosis [44]. Inhibition of GSK-3β in hippocampal neu- rons protected it from radiation-induced apoptosis [9, 70].