Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis.
c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto- and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin- but not TNFalpha-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stress-induced, but not for TNFalpha-induced apoptosis.
Machuy
N
N
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Rajalingam
K
K
Rudel
T
T
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D019085:Fluorescent Antibody Technique, Direct; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011494:Protein Kinases / Q000032:analysis; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D013312:Stress, Physiological; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D011494:Protein Kinases; D016315:Proto-Oncogene Proteins c-abl; D020169:Caspases