Full Activation of PKB/Akt in Response to Insulin or Ionizing Radiation Is Mediated through ATM

Abstract

The gene mutated in ataxia telangiectasia, ATM, has been implicated in several cell functions such as cell cycle control and response to DNA damage and insulin. PKB/Akt has also been implicated in the cellular response to insulin, gamma-radiation, and cell cycle control. Interestingly, lack of PKB/Akt function in vivo is able to mimic some phenotypic abnormalities associated with ataxia telangiectasia (AT). Here we show that ATM is a major determinant of full PKB/Akt activation in response to insulin or gamma-radiation. This effect is mediated through the phosphatidylinositol 3-kinase domain of ATM that specifically affects Akt serine 473 phosphorylation. This conclusion was inferred from the results obtained in transient transfection assays using exogenous PKB/Akt and ATM in Cos cells. Moreover, the use of ATM inhibitors or small interfering RNA confirmed our observation. Further supporting these results, we also observed that biological responses tightly regulated by Akt, such as transcription factor of the forkhead family activity after insulin treatment or gamma-radiation response, were altered in cell lines derived from AT patients and knockout mice for ATM in which phosphorylation in serine 473 was almost abolished. This study proposes new clues in the search of the unknown PDK2 and new explanations for the radiosensitivity or insulin intolerance described more than 30 years ago in AT patients.

DNA-dependent Protein Kinase-mediated Phosphorylation of Protein Kinase B Requires a Specific Recognition Sequence in the C-terminal Hydrophobic Motif

“…We did not detect significant differences in DNA-PK activity in the presence of Mg 2ϩ or Mn 2ϩ (data not shown). Recent observations from ATM Ϫ/Ϫ MEFs or ATM Ϫ/Ϫ , ATR Ϫ/Ϫ double MEFs (31) contrast with the conclusion of Viniegra et al (45), who argued that ATM promotes PKB phosphorylation on Ser-473. It should be noted that ATM Ϫ/Ϫ MEFs in their study were produced from a p53 Ϫ/Ϫ background.…”

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…Secondly, Akt has been shown to be a direct phosphorylation target of ATM, an upstream driver of the DDR (Viniegra et al , 2005). To test the relation between ATM, Akt and mTORC1, we induced a DDR in human fibroblasts by X‐ray irradiation and treated them with an ATM inhibitor.…”

Dexamethasone Partially Rescues Ataxia Telangiectasia-mutated (ATM) Deficiency in Ataxia Telangiectasia by Promoting a Shortened Protein Variant Retaining Kinase Activity

“…Boehrs et al (32) suggest that cytoplasmic ATM promotes neuron survival in an insulin-dependent manner. Viniegra et al suggested that ATM is required for full activation of AKT, the key kinase of the insulin pathway (29). Finally, Kim et al demonstrated that AKT and ERK1/2 are constitutively down-regulated in ATM Ϫ/Ϫ neurospheres (35).…”