S. Kharbanda et al., Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage, MOL CELL B, 20(14), 2000, pp. 4979-4989
The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agen
ts and regulates induction of the stress-activated c-Jun N-terminal protein
kinase (SAPK). Here we show that nuclear c-Abl associates with MEK kinase
1 (MEKK-1), an upstream effector of the SEK1-->SAPK pathway, in the respons
e of cells to genotoxic stress. The results demonstrate that the nuclear c-
Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vi
vo. Transient-transfection studies with wild-type and kinase-inactive c-Abl
demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl a
ctivates MEKK-1 in vitro and in response to DNA damage. The results also de
monstrate that c-AbI induces MEKK-1-mediated phosphorylation and activation
of SEK1-SAPK in coupled kinase assays. These findings indicate that c-Abl
functions upstream of MEKK-1-dependent activation of SAPK in the response t
o genotoxic stress.