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 and cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocalizes with the endoplasmic reticulum (ER)-associated protein grp78. Expression of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellular fractionation studies further indicate that over 20% of cellular c-Abl is detectable in the ER. The results also demonstrate that induction of ER stress with calcium ionophore A23187, brefeldin A, or tunicamycin is associated with translocation of ER-associated c-Abl to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in the response to ER stress by a c-Abl-dependent mechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficient cells. These findings indicate that c-Abl is involved in signaling from the ER to mitochondria and thereby the apoptotic response to ER stress.
Ito
Y
Y
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pandey
P
P
Mishra
N
N
Kumar
S
S
Narula
N
N
Kharbanda
S
S
Saxena
S
S
Kufe
D
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl