Glycogen synthase kinase-3 (GSK-3) is a key downstream target of the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt cell survival pathway. Activation of PI 3-kinase and Akt leads to the inhibition of GSK-3, which is essential for cell survival. Overexpression of active GSK-3 induces apoptosis in Rat-1 and PC12 cells, while dominant-negative GSK-3 prevents apoptosis following PI 3-kinase inhibition. These findings suggest that GSK-3 plays a critical role in regulating apoptosis and is a key component of the PI 3-kinase/Akt survival pathway. The PI 3-kinase/Akt pathway is involved in cell survival by preventing apoptosis. GSK-3 is a physiological target of Akt, and its activity is inhibited by Akt phosphorylation. GSK-3 is involved in various cellular processes, including metabolism, proliferation, and differentiation. It also regulates cell fate in Dictyostelium and is part of the Wnt signaling pathway. Here, we show that GSK-3 is involved in the regulation of apoptosis, identifying it as a critical downstream element of the PI 3-kinase/Akt cell survival pathway. Experiments showed that inhibition of GSK-3 activity is mediated by the PI 3-kinase/Akt signaling pathway during cell survival. Overexpression of active GSK-3 induces apoptosis in PC12 and Rat-1 cells, while dominant-negative GSK-3 prevents apoptosis induced by PI 3-kinase inhibition. These results indicate that GSK-3 is a key target of PI 3-kinase signaling leading to prevention of apoptosis. Overexpression of active GSK-3 is sufficient to induce apoptosis, whereas expression of dominant-negative GSK-3 effectively protects cells from apoptosis resulting from inhibition of PI 3-kinase. These findings implicate GSK-3 as a central element in the PI 3-kinase/Akt survival pathway.Glycogen synthase kinase-3 (GSK-3) is a key downstream target of the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt cell survival pathway. Activation of PI 3-kinase and Akt leads to the inhibition of GSK-3, which is essential for cell survival. Overexpression of active GSK-3 induces apoptosis in Rat-1 and PC12 cells, while dominant-negative GSK-3 prevents apoptosis following PI 3-kinase inhibition. These findings suggest that GSK-3 plays a critical role in regulating apoptosis and is a key component of the PI 3-kinase/Akt survival pathway. The PI 3-kinase/Akt pathway is involved in cell survival by preventing apoptosis. GSK-3 is a physiological target of Akt, and its activity is inhibited by Akt phosphorylation. GSK-3 is involved in various cellular processes, including metabolism, proliferation, and differentiation. It also regulates cell fate in Dictyostelium and is part of the Wnt signaling pathway. Here, we show that GSK-3 is involved in the regulation of apoptosis, identifying it as a critical downstream element of the PI 3-kinase/Akt cell survival pathway. Experiments showed that inhibition of GSK-3 activity is mediated by the PI 3-kinase/Akt signaling pathway during cell survival. Overexpression of active GSK-3 induces apoptosis in PC12 and Rat-1 cells, while dominant-negative GSK-3 prevents apoptosis induced by PI 3-kinase inhibition. These results indicate that GSK-3 is a key target of PI 3-kinase signaling leading to prevention of apoptosis. Overexpression of active GSK-3 is sufficient to induce apoptosis, whereas expression of dominant-negative GSK-3 effectively protects cells from apoptosis resulting from inhibition of PI 3-kinase. These findings implicate GSK-3 as a central element in the PI 3-kinase/Akt survival pathway.