The study investigates the role of glycogen synthase kinase-3 (GSK-3) in the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt cell survival pathway. GSK-3 is a key substrate of Akt, which is inhibited by phosphorylation. Overexpression of catalytically active GSK-3 induced apoptosis in Rat-1 and PC12 cells, while dominant-negative GSK-3 prevented apoptosis following PI 3-kinase inhibition. These findings suggest that GSK-3 plays a critical role in regulating apoptosis and is a key downstream target of the PI 3-kinase/Akt survival signaling pathway. The results also indicate that GSK-3 activity is necessary for apoptosis resulting from PI 3-kinase inhibition, highlighting its central role in the PI 3-kinase/Akt survival pathway.The study investigates the role of glycogen synthase kinase-3 (GSK-3) in the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt cell survival pathway. GSK-3 is a key substrate of Akt, which is inhibited by phosphorylation. Overexpression of catalytically active GSK-3 induced apoptosis in Rat-1 and PC12 cells, while dominant-negative GSK-3 prevented apoptosis following PI 3-kinase inhibition. These findings suggest that GSK-3 plays a critical role in regulating apoptosis and is a key downstream target of the PI 3-kinase/Akt survival signaling pathway. The results also indicate that GSK-3 activity is necessary for apoptosis resulting from PI 3-kinase inhibition, highlighting its central role in the PI 3-kinase/Akt survival pathway.