The long-term scientific goal of my laboratory is to understand the molecular mechanisms that specify retina cell number. Using the compound eye of Drosophila as an experimental model, my laboratory has discovered a novel signaling pathway, the Hippo pathway, which controls retina cell number by coordinately regulating cell proliferation and cell death. Work from my laboratory in the last project period has allowed us to delineate a Hippo kinase cascade comprised of the Ste20-like kinase Hippo (Hpo), the NDR family kinase Warts (Wts), and the transcriptional co activator Yorkie (Yki). Hpo phosphorylates and activates Wts, which in turn, inactivates Yki by phosphorylating the latter at a critical residue (S168) and excluding it from the nucleus, where it normally functions as a co activator for the TEAD/TEF family transcription factor Scalloped (Sd). The Hippo pathway promotes cell death and restricts cell proliferation through the transcriptional regulation of target genes such as the cell cycle regulator cyclin E and the cell death inhibitor diap1. The mammalian homologues of Hpo, Sav, Wts and Yki constitute an analogous kinase cascade and that the mammalian Hippo pathway plays a conserved role in organ size control. Most recently, we have discovered Kibra (Kbr) as a novel tumor suppressor that functions together with Merlin (Mer) and the related FERM domain protein Expanded (Ex) to regulate the Hippo kinase cascade. Since signaling events upstream of Hpo still remain poorly defined, our identification of this novel protein complex provides new opportunities to investigate this less understood aspect of the Hippo signaling pathway. In the coming project period, we propose to build on these findings to further elucidate the composition, function and regulation of the Hippo pathway, through the following lines of research. First, we aim to define a complete Hippo signaling pathway that relays information from the extracellular milieu to Yki phosphorylation by conducting a genome-wide RNAi screens and genetic screens for additional components of the Hippo pathway. Second, we will identify the missing DNA-binding transcription factor(s) that regulates Hippo target gene transcription, since our previous characterization of Sd and Yki suggests that Yki may partner with additional DNA-binding transcription factors to regulate the expression of Hippo target genes. We will test this hypothesis by conducting systematic protein-protein and protein-DNA interaction screens. Lastly, we will investigate the molecular and cellular mechanisms by which the Kbr-Ex-Mer complex functions within the Hippo pathway. Besides revealing fundamental mechanisms of eye development, the proposed studies will have general implications for the development of other tissues.

Public Health Relevance

The proposed studies will not only allow us to elucidate the basic molecular mechanism that regulates retina cell number, but also provide general insights into how cell number is determined in other organs during animal development and how aberrant regulation of this process could lead to tissue atrophy or tumorigenesis. Such insights may facilitate the therapeutic interventions of relevant human diseases, including diseases of the retina.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015708-10
Application #
8512727
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2004-08-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$461,131
Indirect Cost
$179,297
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Qing, Yun; Yin, Feng; Wang, Wei et al. (2014) The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6. Elife 3:
Yin, Feng; Yu, Jianzhong; Zheng, Yonggang et al. (2013) Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154:1342-55
Koontz, Laura M; Liu-Chittenden, Yi; Yin, Feng et al. (2013) The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell 25:388-401
Yu, Jianzhong; Zheng, Yonggang; Dong, Jixin et al. (2010) Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18:288-99
Pan, Duojia (2010) The hippo signaling pathway in development and cancer. Dev Cell 19:491-505
Ling, Chen; Zheng, Yonggang; Yin, Feng et al. (2010) The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A 107:10532-7
Tian, Wei; Yu, Jianzhong; Tomchick, Diana R et al. (2010) Structural and functional analysis of the YAP-binding domain of human TEAD2. Proc Natl Acad Sci U S A 107:7293-8
Alarcon, Claudio; Zaromytidou, Alexia-Ileana; Xi, Qiaoran et al. (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139:757-69
Wu, Shian; Liu, Yi; Zheng, Yonggang et al. (2008) The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14:388-98
Dong, Jixin; Feldmann, Georg; Huang, Jianbin et al. (2007) Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120-33

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