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Molecular and Cellular Biology, July 2000, p. 4979-4989, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Activation of MEK Kinase 1 by the c-Abl Protein Tyrosine Kinase in Response to DNA Damage

Surender Kharbanda,1,* Pramod Pandey,1 Teruo Yamauchi,1 Shailender Kumar,1 Masao Kaneki,1 Vijay Kumar,1 Ajit Bharti,1 Zhi-Min Yuan,1 Louis Ghanem,2 Ajay Rana,2 Ralph Weichselbaum,3 Gary Johnson,4 and Donald Kufe1

Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021151; Diabetes Research Laboratory, Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021142; Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 606373; and Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 802624

Received 23 December 1999/Returned for modification 2 February 2000/Accepted 12 April 2000

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents 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 SEK1right-arrowSAPK pathway, in the response 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 vivo. Transient-transfection studies with wild-type and kinase-inactive c-Abl demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage. The results also demonstrate that c-Abl 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 to genotoxic stress.

* Corresponding author. Mailing address: Dana Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115. Phone: (617) 632-2938. Fax: (617) 632-2934. E-mail: surender_kharbanda{at}dfci.harvard.edu.

Molecular and Cellular Biology, July 2000, p. 4979-4989, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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