The long-term goal of this proposal is to elucidate the molecular mechanism(s) by which the Wingless (Wg) morphogen gradient and signaling are regulated during development. Drosophila Wg encodes an evolutionarily conserved glycoprotein of the Wnt family. Aberant Wg/Wnt signaling activity underlies a number of human developmental disorders and contributes to a variety of cancers. Thus, elucidation of the Wg/Wnt signaling pathway will provide new insights into the mechanisms of related human diseases. Although the components of the Wg/Wnt signaling pathway in its receiving cells have been well characterized over the past 20 years, it remains poorly understood how the mature form of Wg is secreted and travels to its receiving cells to form a concentration gradient, and how the Wg signaling activates the transcription of its downstram target genes. This is an application for continuing support. The current proposal will examine the mechanisms of Wg secretion and its signaling activity in the regulation of the transcription of its target genes. Fist, we will determine the functions of three newly identified ER and Golgi vesicle proteins in Wg secretion (Aim1). Second, we will examine the role(s) of ubiquitin E3 ligase Su (dx) and the deubiquitinating enzyme USP8 in Wls ubiquitination and Wg secretion (Aim2). Third, we will examine the function of Drosophila UBR5 in regulating Wg signaling (Aim3). Taken together, our genetic and biochemical analyses of the newly identified genes in the Wg pathway will provide new insights into the mechanisms of Wg secretion and the transcriptional activation of Wg target genes. Since the Wg signaling transduction pathway is conserved between Drosophila and humans, the outcomes of this project will clearly provide new insights into the mechanisms of various disease processes including cancers.

Public Health Relevance

Wingless (Wg)/ Wnt signaling is essential for embryonic development and is implicated in a variety of human diseases including cancers. This proposal will examine the molecular mechanisms by which Wg secretion and its signaling activity is regulated in development. The outcomes of this application will help in understanding the related human disease processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063891-11
Application #
8449076
Study Section
Intercellular Interactions (ICI)
Program Officer
Hoodbhoy, Tanya
Project Start
2002-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
11
Fiscal Year
2013
Total Cost
$295,290
Indirect Cost
$102,290
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Huang, Q; Tang, X; Wang, G et al. (2014) Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila. Cell Death Differ 21:1961-70
Wang, Guolun; Tang, Xiaofang; Chen, Yujie et al. (2014) Hyperplastic discs differentially regulates the transcriptional outputs of hedgehog signaling. Mech Dev 133:117-25
Feng, Ying; Li, Xue; Ray, Lorraine et al. (2014) The Drosophila tankyrase regulates Wg signaling depending on the concentration of Daxin. Cell Signal 26:1717-24
Zhou, Bo; Yun, Eun-Young; Ray, Lorraine et al. (2014) Retromer promotes immune quiescence by suppressing Spatzle-Toll pathway in Drosophila. J Cell Physiol 229:512-20
You, Jia; Zhang, Yan; Li, Zhouhua et al. (2014) Drosophila perlecan regulates intestinal stem cell activity via cell-matrix attachment. Stem Cell Reports 2:761-9
Zhang, Yan; You, Jia; Ren, Wenyan et al. (2013) Drosophila glypicans Dally and Dally-like are essential regulators for JAK/STAT signaling and Unpaired distribution in eye development. Dev Biol 375:23-32
Tang, Xiaofang; Wu, Yihui; Belenkaya, Tatyana Y et al. (2012) Roles of N-glycosylation and lipidation in Wg secretion and signaling. Dev Biol 364:32-41
Han, Chun; Wang, Denan; Soba, Peter et al. (2012) Integrins regulate repulsion-mediated dendritic patterning of drosophila sensory neurons by restricting dendrites in a 2D space. Neuron 73:64-78
Zhou, Bo; Wu, Yihui; Lin, Xinhua (2011) Retromer regulates apical-basal polarity through recycling Crumbs. Dev Biol 360:87-95
You, Jia; Belenkaya, Tatyana; Lin, Xinhua (2011) Sulfated is a negative feedback regulator of wingless in Drosophila. Dev Dyn 240:640-8

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