Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation

• Published in: Nature (London) Vol. 387; no. 6632; pp. 516 - 519
• Main Authors: Baskaran, R, Wood, L. D, Whitaker, L. L, Canman, C. E, Morgan, S. E, Xu, Y, Barlow, C, Baltimore, D, Wynshaw-Boris, A, Kastan, M. B, Wang, J. Y. J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 29.05.1997; Nature Publishing Group
• Subjects: 3T3 Cells; Animals; Ataxia Telangiectasia - enzymology; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Biological effects of radiation; Cell Cycle; Cell Cycle Proteins; Cell Line, Transformed; Cellular biology; DNA-Binding Proteins; Enzyme Activation - radiation effects; Fundamental and applied biological sciences. Psychology; Gamma Rays; Genes; Health risks; Humans; Ionizing radiation; Ionizing radiations; Medical disorders; Mice; Protein-Serine-Threonine Kinases; Proteins - genetics; Proteins - metabolism; Proto-Oncogene Proteins c-abl - metabolism; RNA Polymerase II - metabolism; Tissues, organs and organisms biophysics; Transfection; Tumor Suppressor Proteins; Immunopathology; Skin disease; Nervous system diseases; Enzyme; Transferases; Rodentia; Cardiovascular disease; Genetic disease; Vascular disease; Signal transduction; Eye disease; Vertebrata; Ionizing irradiation; Mammalia; Mouse; Animal; C-Onc gene; Ataxia telangiectasia; Biological effect; Mutation; Protein-tyrosine kinase; Protooncogene
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/387516a0

Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or protein kinase. Most of the human AT patient phenotypes are recapitulated in Atm-deficient mice. Cells derived from Atm-/- mice, like those from AT patients, exhibit abnormal response to ionizing radiation. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl proto-oncogene. Ionizing radiation does not activate c-Abl in cells from AT patients or in thymocytes or fibroblasts from the Atm-deficient mice. Ectopic expression of a functional ATM kinase domain corrects this defect, as it phosphorylates the c-Abl tyrosine kinase in vitro at Ser 465, leading to the activation of c-Abl. A mutant c-Abl with Ser 465 changed to Ala 465 is not activated by ionizing radiation or ATM kinase in vivo. These findings identify the c-Abl tyrosine kinase as a downstream target of phosphorylation and activation by the ATM kinase in the cellular response to ionizing radiation.