Consequences of Shb and c-Abl interactions for cell death in response to various stress stimuli.
The adaptor protein Shb has previously been shown to regulate apoptosis in response to cytokines and inhibitors of angiogenesis although the mechanisms governing these effects have remained obscure. We currently demonstrate interactions between Shb and c-Abl and that Shb regulates c-Abl kinase activity. The data suggest that c-Abl binds to tyrosine phosphorylated Shb via a concerted effort involving both the c-Abl SH3 and SH2 domains. The biological significance of the Shb/c-Abl interaction was presently tested in overexpression experiments and was found to promote hydrogen peroxide-induced cell death. We also show by Shb knockdown experiments that Shb regulates c-Abl activity and modulates cell death in response to the genotoxic agent cisplatin and the endoplasmic reticulum stress-inducer tunicamycin. The findings are in agreement with the notion of Shb playing a pivotal role in modulating c-Abl pro-apoptotic signaling in response to various stress stimuli.
Hägerkvist
Robert
R
Department of Medical Cell Biology, Uppsala University, Biomedicum, PO Box 571, Husargatan 3, S-751 23 Uppsala, Sweden.
Mokhtari
Dariush
D
Lindholm
Cecilia
C
Farnebo
Filip
F
Mostoslavsky
Gustavo
G
Mulligan
Richard C
RC
Welsh
Nils
N
Welsh
Michael
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D006801:Humans; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D014415:Tunicamycin / Q000633:toxicity; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D011518:Proto-Oncogene Proteins; C490081:SHB protein, human; D014415:Tunicamycin; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin