Cell signaling plays a central role in embryonic development and adult tissue homeostasis and its deregulation can lead to human diseases such as cancer. Therefore, understanding how extracellular signals are integrated to control cell growth and patterning during development, and how they coordinate stem cell activity in tissue homeostasis is of central importance in biomedical research. Our overarching goal is to understand how signaling networks control organ development and regeneration, with an emphasis on Hedgehog (Hh) and Hippo (Hpo) signaling pathways. Hh signaling controls many key developmental processes in species ranging from Drosophila to human and its abnormal activity has been implicated in numerous human cancers including medulloblastoma and basal cell carcinoma. Hh acts through a conserved signaling cascade emanating from the receptor-like molecule Smoothened (Smo) to the transcription factor Ci/Gli. However, the molecular mechanism underlying Hh signal transduction is not fully understood. In this study, we will investigate how Smo cell surface expression and activity are regulated by post-translational modifications (PTMs), and how Smo regulates the downstream signaling complexes to convert Ci/Gli from a repressor to an activator. The Hpo pathway is a newly identified tumor suppressor pathway that controls tissue growth and organ size by simultaneously regulating cell growth, proliferation, and apoptosis. Deregulation of Hpo pathway activity has also been implicated in many types of human cancer. Despite its central importance in development and diseases, the molecular mechanism underlying Hpo pathway regulation remains poorly understood. We have developed a genetic modifier screen allowing us to identify novel pathway regulators. We will extend the screen and investigate the mechanisms by which the identified new components regulate Hpo pathway activity. We also study the role of Hh, Hpo and other signaling pathways in adult tissue homeostasis and regeneration. Drosophila adult midgut has emerged as an attractive model to study how the self-renewal, proliferation and differentiation of stem cells are coordinated, not only because the cell lineage of the midgut is relatively simple and well defined, but also because conserved genetic pathways and regulatory mechanisms are utilized in this system. We have demonstrated that intestinal stem cells (ISCs) in the midgut can be activated in response to tissue damage induced by chemicals, and uncovered the role of multiple signaling pathways, including Insulin, Hpo, and Hh pathways, in the regulation of ISC activity during midgut regeneration. In addition, we have identified the epithelia-derived BMP as a niche signal for ISC self-renewal. In the proposed study, we will investigate how the niche signals are dynamically regulated and integrated to control ISC self-renewal, proliferation and differentiation. The knowledge gained from this study will have important implications for developmental biology, cancer biology and regenerative medicine.

Public Health Relevance

Conserved cell signaling pathways such Hh and Hpo pathways play essential roles in embryonic development and adult tissue homeostasis. Deregulation of Hh and Hpo pathway activities has also been implicated in many types of human cancer. Understanding how Hh and Hpo pathways are regulated and how these and other signaling pathways are integrated to control cell growth and patterning during embryonic development as well as stem cell activity in adult tissue homeostasis and regeneration should not only provide novel insights into the etiology of human cancer, because cancer cells are derived from stem/progenitor cells that hijack these control mechanisms, but may also provide new avenues for therapeutic treatment of cancers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Melillo, Amanda A
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University of Texas Sw Medical Center Dallas
Anatomy/Cell Biology
Schools of Medicine
United States
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Cho, Yong Suk; Zhu, Jian; Li, Shuangxi et al. (2018) Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K. Nat Commun 9:1657
Li, Shuang; Cho, Yong Suk; Wang, Bing et al. (2018) Regulation of Smoothened ubiquitylation and cell surface expression through a Cul4-DDB1-G? E3 ubiquitin ligase complex. J Cell Sci 131:
Li, Shuang; Li, Shuangxi; Wang, Bing et al. (2018) Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases. Sci Signal 11:
Tian, Aiguo; Wang, Bing; Jiang, Jin (2017) Injury-stimulated and self-restrained BMP signaling dynamically regulates stem cell pool size during Drosophila midgut regeneration. Proc Natl Acad Sci U S A 114:E2699-E2708
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Chen, Ping; Zhou, Zizhang; Yao, Xia et al. (2017) Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A. Sci Rep 7:2891
Ma, Guoqiang; Li, Shuang; Han, Yuhong et al. (2016) Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway. Dev Cell 39:438-451

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