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.