Targeting of the c-Abl Tyrosine Kinase to Mitochondria in Endoplasmic Reticulum Stress-Induced Apoptosis

doi:10.1128/MCB.21.18.6233-6242.2001

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Molecular and Cellular Biology, September 2001, p. 6233-6242, Vol. 21, No. 18
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.18.6233-6242.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeting of the c-Abl Tyrosine Kinase to Mitochondria in Endoplasmic Reticulum Stress-Induced Apoptosis

Yasumasa Ito,¹ Pramod Pandey,¹ Neerad Mishra,² Shailendra Kumar,¹ Navneet Narula,³ Surender Kharbanda,¹ Satya Saxena,² and Donald Kufe¹^,^*

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115¹; Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87115²; and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4282³

Received 2 March 2001/Returned for modification 4 April 2001/Accepted 15 June 2001

The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus and cytoplasm. Using confocal microscopy, we demonstratedthat c-Abl colocalizes with the endoplasmic reticulum (ER)-associatedprotein grp78. Expression of c-Abl in the ER was confirmed byimmunoelectron microscopy. Subcellular fractionation studies furtherindicate that over 20% of cellular c-Abl is detectable in theER. The results also demonstrate that induction of ER stress withcalcium ionophore A23187, brefeldin A, or tunicamycin is associatedwith translocation of ER-associated c-Abl to mitochondria. Inconcert with targeting of c-Abl to mitochondria, cytochrome cis released in the response to ER stress by a c-Abl-dependentmechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficientcells. These findings indicate that c-Abl is involved in signalingfrom the ER to mitochondria and thereby the apoptotic responseto ERstress.

^* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. Phone: (617)632-3141. Fax: (617) 632-2934. E-mail: Donald_Kufe{at}dfci.harvard.edu.

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