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

R. Baskaran, L. D. Wood, L. L. Whitaker, C. E. Canman, S. E. Morgan, Y. Xu, C. Barlow, D. Baltimore, A. Wynshaw-Boris, M. B. Kastan and J. Y. J. Wang
Additional contact information
R. Baskaran: University of California at San Diego
L. D. Wood: University of California at San Diego
L. L. Whitaker: University of California at San Diego
C. E. Canman: The Johns Hopkins Oncology Center
S. E. Morgan: The Johns Hopkins Oncology Center
Y. Xu: Massachusetts Institute of Technology
C. Barlow: NCHGR, NIH
D. Baltimore: Massachusetts Institute of Technology
A. Wynshaw-Boris: NCHGR, NIH
M. B. Kastan: The Johns Hopkins Oncology Center
J. Y. J. Wang: University of California at San Diego

Nature, 1997, vol. 387, issue 6632, 516-519

Abstract: 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.

Date: 1997
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DOI: 10.1038/387516a0

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