ATM kinase signals to diverse metabolic pathways in the cytoplasm. During in vitro experiments, oxidants/prooxidants induce the phosphorylation and activation of ATM dimers that appear to be linked via intermolecular disulfide bonds formed at a conserved C2991 residue in the C- terminus.66 It remains to be fully clarified whether these ATM dimers are similarly activated in response to endogenously generated ROS—acting directly on ATM, or else via the platelet-derived growth factor receptor β67 —and are responsible for regulating (1) expression of mTORC1; (2) synthesis of reduced glutathione (GSH) via the PPP; and (3) insulin-induced protein synthesis in response to oxidative stress. Nevertheless, the activation of ATM in response to oxidative stress leads to the inhibition of mTORC1 activity via the LKB1/AMPK/TSC2 signaling cascade. Activated ATM phosphorylates LKB1 (Thr366), which in turn phosphorylates AMPK (Thr172). AMPK subsequently phosphorylates TSC2 (Thr1271, Ser1387), which inhibits the expression of mTORC1, thereby promoting autophagy.68,-70 Furthermore, ATM regulates TSC2 activity in response to hypoxia by directly phosphorylating HIF1α (Ser696),71 and hence blocks mTORC1 activity. In addition, activated ATM induces complex formation between glucose-6-phosphate dehydrogenase (G6PD) and Hsp27, which increases the production of NADPH via the PPP, resulting in elevated intracellular levels of the antioxidant glutathione.72 Cytoplasmic ATM also regulates protein synthesis in response to insulin by phosphorylating 4E-BP1 (Ser111) and enhancing mRNA translation.73 Moreover, ATM phosphorylates Akt (Ser473) in response to insulin, which stimulates the translocation of the glucose transporter 4 (GLUT4) complex into the cell membrane via an as yet undetermined mechanism.74,75
