Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation

Hypoxia initiates numerous intracellular signaling pathways important in re gulating cell proliferation, differentiation, and death. In this study, we investigated the pathway that hypoxia uses to activate Akt and inactivate g lycogen synthase kinase-3 (GSK-3), two proteins the functions of which are important in cell survival and energy metabolism. Severe hypoxia (0.01% oxy gen) initiated a signaling cascade by inducing the tyrosine phosphorylation of the platelet-derived growth factor (PDGF) receptor within 1 h of treatm ent and increasing receptor association with the p85 subunit of phosphatidy linositol 3-kinase (PI 3-K), Hypoxia-induced signaling also resulted in PI 3-K-dependent phosphorylation of Akt on Ser-473, a modification of Akt that is important for its activation. This activation of Akt by hypoxia was sub stantially diminished in cells that possessed mutations in their PDGF recep tor-PI 3-K interaction domain. In addition, Akt activation by hypoxia was r esistant to treatment with the growth factor receptor poison suramin but wa s sensitive to treatment with the PI 3-K inhibitor wortmannin. Activation o f Akt by hypoxia resulted in the phosphorylation of GSK-3 alpha and GSK-3 b eta at Ser-9 and Ser-21, two well-documented Akt phosphorylation sites, res pectively, that are inactivating modifications of each GSK3 isoform. In sup port of the phosphorylation data, GSK-3 activity was significantly reduced under hypoxia. In conclusion, we propose that hypoxia activates a growth fa ctor receptor/PI 3-K/Akt cascade that leads to GSK-3 inactivation, a pathwa y that can impact cell survival, proliferation, and metabolism.