The Hippo Pathway targets the Cdh1/fzr inhibitor Rae1 to regulate mitosis and establish organ size homeostasis. Maryam Jahanshahi¹, Kuangfu Hsiao², Andreas Jenny³, Cathie Pfleger¹. 1) Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY; 2) Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York NY; 3) Department of Molecular and Developmental Biology, Albert Einstein College of Medicine, Bronx NY.

   The Hippo Tumor Suppressor pathway serves as a master regulatory axis which coordinates proliferation, growth, and apoptosis to establish and maintain appropriate organ size. It is well established that loss of pathway components promotes cell division, cell death resistance, and tumor-like overgrowth in both Drosophila and vertebrates. Loss of Hippo Pathway activity is also implicated in initiation and progression of a range of cancers including colorectal cancer, liver cancer, melanoma, lung cancer, leukemias, and ovarian cancer. Therefore the Hippo pathway has an essential role in organ size regulation and tumorigenesis. Although it is clear how the pathway promotes cell death resistance, crucial targets responsible for the distinct functions of restricting growth and restricting cell proliferation and specific effectors responsible for coordinating organ size and proliferation remain largely unknown. We have identified the Cdh1-inhibitor Rae1 at the nexus within the Hippo Pathway integrating proliferation and organ size. Exogenous Rae1 increases both cell proliferation and organ size. Rae1 is required in vivo for S-phase entry and mitotic progression and is phosphorylated and degraded upon activation of Hippo signaling. We propose a model that Hippo signaling promotes Cdh1-Anaphase Promoting Complex/Cyclosome activity by relieving its Rae1-mediated inhibition. Importantly, Rae1 reduction compromises survival of Hippo-deficient tissue indicating synthetic lethality and a requirement for Rae1 reminiscent of oncogene/non-oncogene addiction. The Rae1 addiction of tissue upon loss of Hippo pathway activity further implicates Rae1 in tumorigenesis and suggests that Rae1 may represent a therapeutic target for cancers in which Hippo signaling is dysregulated.