FIGURE 7.

In astrocytes, IGF-I induces the stimulation of the prosurvival kinase AKT by the activation of a signaling cascade that includes IRS-1 phosphorylation, translocation of PI3K to the membrane (allowing PIP₃ generation and AKT recruitment), and activation of AKT by PDK1/mTORC2 kinases. Oxidative stress (generated by an uncontrollable ROS increase) can induce redox activation of p38 kinase in several cells types. In neurons, p38 induces IGF-I resistance, preventing IRS-1 phosphorylation by IGF-I receptor IGF-IR, whereas in astrocytes, this response is not present. Furthermore, IGF-I induces only in astrocytes the inactivation of the phosphatase PTEN (by inducing its phosphorylation and cytosolic translocation), preserving in this way generation of PIP₃ and AKT activation in both normal and oxidative stress conditions. Armoring of AKT activation by IGF-I increases astrocyte survival during oxidative stress through inactivation of the proapoptotic FOXO3 transcription factor (by its phosphorylation by AKT and by inactivation of JNKs) and stimulation of ROS-detoxifying enzymes. Furthermore, AKT activation is also necessary to preserve the neuroprotective action of astrocytes.