Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1.
The ablation of the protein kinase Raf-1 renders cells hypersensitive to apoptosis despite normal regulation of extracellular signal-regulated kinases, which suggests that apoptosis protection is mediated by a distinct pathway. We used proteomic analysis of Raf-1 signaling complexes to show that Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2). Raf-1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity. Depletion of MST2 from Raf-1-/- mouse or human cells abrogated sensitivity to apoptosis, whereas overexpression of MST2 induced apoptosis. Conversely, depletion of Raf-1 from Raf-1+/+ mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both Raf-1 and MST2 prevented apoptosis.
O'Neill
Eric
E
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Rushworth
Linda
L
Baccarini
Manuela
M
Kolch
Walter
W
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism; D000099317:Hippo Kinases
D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf; D034741:RNA, Small Interfering; D000090742:Serine-Threonine Kinase 3; D019311:Staurosporine; D019014:fas Receptor; C000715470:MAS1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse