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Elucidation of a Universal Size-Control Mechanism in Drosophila and Mammals
Jixin Dong,1 Georg Feldmann,2 Jianbin Huang,4 Shian Wu,1 Nailing Zhang,1 Sarah A. Comerford,5 Mariana F. Gayyed,3 Robert A. Anders,3 Anirban Maitra,2 and Duojia Pan1,
1 Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
5 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Corresponding author
Duojia Pan
Coordination of cell proliferation and cell death is essential to attain proper organ size during development and for maintaining tissue homeostasis throughout postnatal life. In Drosophila, these two processes are orchestrated by the Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yorkie (Yki). Here we demonstrate that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway. Hippo-mediated phosphorylation inactivates Yki by excluding it from the nucleus, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. We further delineate a mammalian Hippo signaling pathway that culminates in the phosphorylation of YAP, the mammalian homolog of Yki. Using a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent regulator of organ size, and that its dysregulation leads to tumorigenesis. These results uncover a universal size-control mechanism in metazoan.
