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Taming the Hippo: Raf-1 Controls Apoptosis by Suppressing MST2/Hippo

The Raf-1 kinase has a well established role in activating the MEK-ERK/MAPK pathway.However, accumulating evidence including the phenotype of Raf-1-/- mice suggested thatRaf-1 may have other functions independent of its role as MEK activator, in particularpertaining to protection against apoptosis. We have recently demonstrated a new role of Raf-1 by showing that Raf-1 controls the proapoptotic kinase MST2/Hippo. In mammalian cellsMST2 is activated by stress signals and causes apoptosis when overexpressed. Its Drosophilahomologue Hippo regulates apoptosis and cell cycle arrest during differentiation. Raf-1inhibits MST2 by preventing its dimerisation and recruiting a phosphatase that removesactivating phosphorylations on MST2. Both functions require Raf-1 binding to MST2, butare independent of Raf-1’s kinase activity and the ERK pathway. Downregulation of MST2by siRNA reverts the apoptosis hypersensitivity of Raf-1-/- mouse fibroblasts. In contrast, thedownregulation of Raf-1 in Raf-1+/+ cells and human cancer cell lines enhances susceptibilityto Fas induced apoptosis, which is rescued by concomitant downregulation of both Raf-1 andMST2. The MST2:Raf-1 complex is dissociated by stress signals as well as mitogens. Stresssignals robustly activate MST2 and trigger apoptosis. Mitogens only make MST2 permissivefor activation by releasing it from Raf-1, and in addition activate survival pathways allowingproliferation. Thus, by linking mitogenic and apoptotic signalling the MST:Raf-1 complexmay serve as a safeguard against unlicensed proliferation.