The ATM protein kinase and cellular redox signaling: beyond the DNA damage response

Abstract

The ataxia-telangiectasia mutated (ATM) protein kinase is best known for its role in the DNA damage response, but recent findings suggest that it also functions as a redox sensor that controls the levels of reactive oxygen species in human cells. Here, we review evidence supporting the conclusion that ATM can be directly activated by oxidation, as well as various observations from ATM-deficient patients and mouse models that point to the importance of ATM in oxidative stress responses. We also discuss the roles of this kinase in regulating mitochondrial function and metabolic control through its action on tumor suppressor p53, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor 1 (HIF1), and how the regulation of these enzymes may be affected in ATM-deficient patients and in cancer cells.

Figure 1

The ATM protein kinase. The C-terminal PI3 kinase-like kinase domain (KD), spanning aa ~2712 to 2962, is flanked by the domains FAT (FRAP, ATM and TRRAP; ~ aa 1960 to 2566) and FATC (FRAP, ATM and TRRAP C-terminal; ~ aa 2963 to 3056). The N-terminal region of the FATC domain has also been termed the “PIKK-regulatory domain” [5]. The location of autophosphorylation sites in ATM (S367, S1893, S1981 and S2996) [12, 24, 87] is shown. The N-terminus of ATM is composed of HEAT (Huntingtin, elongation factor 1A, protein phosphatase 2A A-subunit, TOR) repeats [88].

Figure 2

ATM interaction with metabolic signaling pathways. ATM is required for NF-κB activation following exposure to ionizing radiation (IR) and reactive oxygen species (ROS) via a mechanism that requires the export of ATM from the nucleus to the cytoplasm [61]. ATM-deficient cells exhibit reduced levels of insulin-like growth factor-I receptor (IGF-IR), a defect that is rescued by expression of ATM cDNA [52, 89]. However, the mechanisms linking ATM to IGF-IR expression are unknown. ATM is required for full activation of AKT in response to insulin and IR treatment [–55, 90, 91], which induces AKT phosphorylation at Ser473 and translocation of glucose transporter 4 (GLUT4) through unknown mechanisms. Inhibition of this pathway induces apoptosis in cancer cells with high AKT activity [55]. Increased activity of glucose-6-phosphate dehydrogenase (G6PD) is observed in the presence of ATM, which promotes NADPH formation and reduction of glutathione [78]. In response to IR treatment and elevated ROS levels, ATM phosphorylates p53 at Ser15 [22]. ROS-induced p53 phosphorylation either induces apoptosis or reduces ROS levels through upregulation of sestrin proteins (which regenerate peroxiredoxins [56, 57]), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) [92]. Mutation of Ser15 in p53 to Ala15 results in elevated ROS levels, leading to insulin resistance and impaired glucose metabolism [56]. Signaling pathways initiated by IR, insulin, and ROS are indicated by black, blue, and red arrows, respectively.

Figure 3

ATM regulates mTORC1 activity through AMPK in response to elevated ROS levels. Elevated ROS levels activate ATM, which in turn phosphorylates and activates LKB1 at Thr366, which then phosphorylates and activates AMPK at Thr172 [62]. AMPK is also activated by IGF-1 [64] and the AMPK activator AICAR [63] in an ATM-dependent and LKB1-independent manner. AMPK phosphorylates TSC2 at multiple sites, which results in TCS2 activation, and then active TCS2 inhibits mTORC1 activity [66]. In addition, ATM directly phosphorylates HIF-1α (one of the subunits of HIF-1), which also promotes TSC2 activity and therefore blocks mTORC1 [82]. Moreover, mTORC1 promotes the expression of HIF-1 [82] and, as part of the larger mTOR complex, regulates cellular growth and protein synthesis. Inhibition of mTORC1 activity by TSC2 induces autophagy, a catabolic process that functions as a cellular salvaging pathway during periods of reduced energy supplies within the cell. Autophagy also functions as a tumor suppression pathway by inhibiting cellular growth. Unregulated mTORC1 activity might lead to cancer by promoting excessive cellular growth and cell division. In addition, high levels of mTORC1 activity result in increased ROS production in mitochondria by increasing oxidative metabolism through expression of the mitochondrial transcriptional regulator PGC-1α and other mechanisms [82, 93]. Therefore, ATM activation by the excess ROS generated by high mTORC1 activity may function as a feedback mechanism to regulate mTORC1 activity.