Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced Apoptosis

The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus a nd cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocal izes with the endoplasmic reticulum (ER)-associated protein grp78. Expressi on of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellul ar fractionation studies further indicate that over 20% of cellular c-Abl i s detectable in the ER. The results also demonstrate that induction of ER s tress with calcium ionophore A23187, brefeldin A, or tunicamycin is associa ted with translocation of ER-associated c-Abl to mitochondria. In concert w ith targeting of c-Abl to mitochondria, cytochrome c is released in the res ponse to ER stress by a c-Abl-dependent mechanism, and ER stress-induced ap optosis is attenuated in c-Abl-deficient cells. These findings indicate tha t c-Abl is involved in signaling from the ER to mitochondria and thereby th e apoptotic response to ER stress.