Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins.
Apoptosis signal-regulating kinase 1 (ASK1) is a pivotal component of a signaling pathway induced by many death stimuli, including tumor necrosis factor alpha, Fas, and the anticancer drugs cisplatin and paclitaxel. Here we report that ASK1 proapoptotic activity is antagonized by association with 14-3-3 proteins. We found that ASK1 specifically bound 14-3-3 proteins via a site involving Ser-967 of ASK1. Interestingly, overexpression of 14-3-3 in HeLa cells blocked ASK1-induced apoptosis whereas disruption of the ASK1/14-3-3 interaction dramatically accelerated ASK1-induced cell death. Targeting of ASK1 by a 14-3-3-mediated survival pathway may provide a novel mechanism for the suppression of apoptosis.
Department of Pharmacology, Cell, and Developmental Biology, Emory University, Atlanta, GA 30322, USA.
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Zhang
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Chen
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Fu
D048948:14-3-3 Proteins; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D053938:DNA Fragmentation / Q000235:genetics; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; D008164:Luminescent Proteins; D011506:Proteins; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human