Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation (original) (raw)

• Letter
• Published: 29 May 1997
• L. D. Wood1,
• L. L. Whitaker1,
• C. E. Canman2,
• S. E. Morgan2,
• Y. Xu3,
• C. Barlow4,
• D. Baltimore3,
• A. Wynshaw-Boris4,
• M. B. Kastan2 &
• …
• J. Y. J. Wang1

Nature volume 387, pages 516–519 (1997)Cite this article

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Abstract

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 kinase1,2. Most of the human AT patient phenotypes are recapitulated in _Atm_-deficient mice3,4. Cells derived from _Atm_-/- mice, like those from AT patients, exhibit abnormal response to ionizing radiation3,5,6. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl/proto-oncogene7,8. 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.

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Authors and Affiliations

1. Department of Biology and Center for Molecular Genetics, University of California at San Diego, La Jolla, California, 92093-0322, USA
   R. Baskaran, L. D. Wood, L. L. Whitaker & J. Y. J. Wang
2. The Johns Hopkins Oncology Center, Baltimore, Maryland, 21205, USA
   C. E. Canman, S. E. Morgan & M. B. Kastan
3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139-4307, USA
   Y. Xu & D. Baltimore
4. Laboratory of Genetic Disease Research, NCHGR, NIH, Bethesda, Maryland, 20892, USA
   C. Barlow & A. Wynshaw-Boris

Authors

1. R. Baskaran
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2. L. D. Wood
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3. L. L. Whitaker
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4. C. E. Canman
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5. S. E. Morgan
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6. Y. Xu
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7. C. Barlow
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8. D. Baltimore
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9. A. Wynshaw-Boris
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10. M. B. Kastan
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11. J. Y. J. Wang
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Baskaran, R., Wood, L., Whitaker, L. et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation.Nature 387, 516–519 (1997). https://doi.org/10.1038/387516a0

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• Received: 13 January 1997
• Accepted: 18 April 1997
• Issue Date: 29 May 1997
• DOI: https://doi.org/10.1038/387516a0

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