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 that Raf-1 may have other functions independent of its role as MEK activator, in particular pertaining 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 cells MST2 is activated by stress signals and causes apoptosis when overexpressed. Its Drosophila homologue Hippo regulates apoptosis and cell cycle arrest during differentiation. Raf-1 inhibits MST2 by preventing its dimerisation and recruiting a phosphatase that removes activating phosphorylations on MST2. Both functions require Raf-1 binding to MST2, but are independent of Raf-1's kinase activity and the ERK pathway. Downregulation of MST2 by siRNA reverts the apoptosis hypersensitivity of Raf-1(-/-) mouse fibroblasts. In contrast, the downregulation of Raf-1 in Raf-1(+/+) cells and human cancer cell lines enhances susceptibility to Fas induced apoptosis, which is rescued by concomitant downregulation of both Raf-1 and MST2. The MST2:Raf-1 complex is dissociated by stress signals as well as mitogens. Stress signals robustly activate MST2 and trigger apoptosis. Mitogens only make MST2 permissive for activation by releasing it from Raf-1, and in addition activate survival pathways allowing proliferation. Thus, by linking mitogenic and apoptotic signalling the MST:Raf-1 complex may serve as a safeguard against unlicensed proliferation.
O'Neill
Eric
E
The Beatson Institute for Cancer Research, Glasgow, UK.
Kolch
Walter
W
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism; D008954:Models, Biological; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000099317:Hippo Kinases
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D034741:RNA, Small Interfering; D000090742:Serine-Threonine Kinase 3; C097835:STK3 protein, human; D000099317:Hippo Kinases; C499474:hpo protein, Drosophila