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

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.