title: The Hippo Pathway Targets Rae1 to Regulate Mitosis and Organ Size and to Feed Back to Regulate Upstream Components Merlin, Hippo, and Warts.
abstract: Hippo signaling acts as a master regulatory pathway controlling growth, proliferation, and apoptosis and also ensures that variations in proliferation do not alter organ size. How the pathway coordinates restricting proliferation with organ size control remains a major unanswered question. Here we identify Rae1 as a highly-conserved target of the Hippo Pathway integrating proliferation and organ size. Genetic and biochemical studies in Drosophila cells and tissues and in mammalian cells indicate that Hippo signaling promotes Rae1 degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size while Rae1 over-expression increases cyclin B levels and organ size, similar to Hippo Pathway over-activation or loss-of-function, respectively. Importantly, Rae1 regulation by the Hippo Pathway is crucial for its regulation of cyclin B and organ size; reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo Pathway loss. Surprisingly, in addition to suppressing overgrowth, reducing Rae1 also compromises survival of epithelial tissue overgrowing due to loss of Hippo signaling leading to a tissue "synthetic lethality" phenotype. Excitingly, Rae1 plays a highly conserved role to reduce the levels and activity of the Yki/YAP oncogene. Rae1 increases activation of the core kinases Hippo and Warts and plays a post-transcriptional role to increase the protein levels of the Merlin, Hippo, and Warts components of the pathway; therefore, in addition to Rae1 coordinating organ size regulation with proliferative control, we propose that Rae1 also acts in a feedback circuit to regulate pathway homeostasis.
authors: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Maryam
authors: 0000-0003-3469-6280
authors: M
authors: Jahanshahi
authors: The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Kuangfu
authors: 0000-0003-0753-9335
authors: K
authors: Hsiao
authors: Department of Developmental and Molecular Biology and Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
authors: Andreas
authors: A
authors: Jenny
authors: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Cathie M
authors: CM
authors: Pfleger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019926:Cyclin B / Q000235:genetics; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008938:Mitosis / Q000235:genetics; D025581:Neurofibromin 2 / Q000096:biosynthesis / Q000235:genetics*; D034521:Nuclear Matrix-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D009929:Organ Size; D010641:Phenotype; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D000072020:Synthetic Lethal Mutations / Q000235:genetics; D014921:Wings, Animal / Q000254:growth & development; D000099317:Hippo Kinases
chemical_list: D019926:Cyclin B; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D025581:Neurofibromin 2; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C490523:Rae1 protein, Drosophila; C099885:merlin, Drosophila; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases