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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Mariani, Andrew P
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Johns Hopkins University
Schools of Medicine
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Yu, Jianzhong; Pan, Duojia (2018) Validating upstream regulators of Yorkie activity in Hippo signaling through scalloped-based genetic epistasis. Development 145:
Zheng, Yonggang; Liu, Bo; Wang, Li et al. (2017) Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex. Cell Rep 21:3612-3623
Das, Arupratan; Fischer, Robert S; Pan, Duojia et al. (2016) YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing. J Biol Chem 291:6096-110
Liu, Bo; Zheng, Yonggang; Yin, Feng et al. (2016) Toll Receptor-Mediated Hippo Signaling Controls Innate Immunity in Drosophila. Cell 164:406-19
Chan, PuiYee; Han, Xiao; Zheng, Baohui et al. (2016) Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat Chem Biol 12:282-9
Deng, Hua; Wang, Wei; Yu, Jianzhong et al. (2015) Spectrin regulates Hippo signaling by modulating cortical actomyosin activity. Elife 4:e06567
Zheng, Yonggang; Wang, Wei; Liu, Bo et al. (2015) Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade. Dev Cell 34:642-55
Pan, Duojia (2015) YAPing Hippo Forecasts a New Target for Lung Cancer Prevention and Treatment. J Clin Oncol 33:2311-3
Ni, Lisheng; Zheng, Yonggang; Hara, Mayuko et al. (2015) Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling. Genes Dev 29:1416-31
Chen, Qian; Zhang, Nailing; Xie, Rui et al. (2015) Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev 29:1285-97

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