Caspase-dependent cleavage of c-Abl contributes to apoptosis.
The nonreceptor tyrosine kinase c-Abl may contribute to the regulation of apoptosis. c-Abl activity is induced in the nucleus upon DNA damage, and its activation is required for execution of the apoptotic program. Recently, activation of nuclear c-Abl during death receptor-induced apoptosis has been reported; however, the mechanism remains largely obscure. Here we show that c-Abl is cleaved by caspases during tumor necrosis factor- and Fas receptor-induced apoptosis. Cleavage at the very C-terminal region of c-Abl occurs mainly in the cytoplasmic compartment and generates a 120-kDa fragment that lacks the nuclear export signal and the actin-binding region but retains the intact kinase domain, the three nuclear localization signals, and the DNA-binding domain. Upon caspase cleavage, the 120-kDa fragment accumulates in the nucleus. Transient-transfection experiments show that cleavage of c-Abl may affect the efficiency of Fas-induced cell death. These data reveal a novel mechanism by which caspases can recruit c-Abl to the nuclear compartment and to the mammalian apoptotic program.
Barilà
Daniela
D
Dulbecco Telethon Institute and Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy. Daniela.Barila@uniroma2.it
Rufini
Alessandra
A
Condò
Ivano
I
Ventura
Natascia
N
Dorey
Karel
K
Superti-Furga
Giulio
G
Testi
Roberto
R
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D011994:Recombinant Proteins; D019014:fas Receptor; D016315:Proto-Oncogene Proteins c-abl; D020169:Caspases