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Science 306 (5705): 2267-2270

Copyright © 2004 by the American Association for the Advancement of Science

Role of the Kinase MST2 in Suppression of Apoptosis by the Proto-Oncogene Product Raf-1

Eric O'Neill,1 Linda Rushworth,1 Manuela Baccarini,3 Walter Kolch1,2*

Abstract: 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.

1 The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2 Sir Henry Wellcome Functional Genomics Facility, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
3 Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Microbiology and Genetics, University of Vienna, Dr. Bohr Gasse 9, A-1030 Vienna, Austria.

* To whom correspondence should be addressed. E-mail: wkolch{at}beatson.gla.ac.uk

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