The Hedgehog (Hh) family of secreted signaling proteins governs cell growth and patterning in numerous developmental processes in both vertebrates and invertebrates. Misregulation of Hh signaling activity has been implicated in many human disorders including cancer. The long-term goal of my laboratory is to understand how Hh controls cell growth and patterning, and how the graded Hh signals are transduced to elicit different developmental outcomes. The Hh signal reception system consists of two transmembrane proteins: a twelve-transmembrane protein Patched (Ptc) as the Hh receptor and a seven-transmembrane protein Smoothened (Smo) as the obligatory signal transducer. We have discovered that protein kinase A (PKA) and casein kinase 1 (CK1) positively regulate the Hh pathway by phosphorylating Smo, leading to its cell surface accumulation and conformational change to an active state. In addition, we found that Hh-induced phosphorylation promotes Smo interaction with the intracellular signaling complexes. We have also found that mammalian Smo undergoes a conformational change in response to Shh, which is regulated by a distinct set of kinases. These and other findings unveil interesting parallels between Drosophila and vertebrate Hh signaling mechanisms and provide new tools and hypotheses to dissect the Hh signaling mechanism in both systems. In this proposal, we will investigate the function and regulation of multiple Smo phosphorylation events in Hh signaling (Aim1), determine how phosphorylation regulates Smo cell surface expression (Aim 2), determine how Smo activates the intracellular signaling complex (Aim 3), and investigate the function and mechanism of Smo phosphorylation in Shh pathway activation (Aim 4). The proposed study should provide deeper understanding of the Hh signal transduction mechanism and shed new light into how graded Hh signals are translated into different developmental outcomes in both Drosophila and vertebrate systems. As abnormal elevation of Smo activity and Hh signaling contributes to many human cancers and Smo is a primary therapeutic target for drug development, our study may provide new avenues for improving diagnosis and therapeutics of Hh pathway related cancers.

Public Health Relevance

Misregulation of Hh pathway activity has been implicated in many human disorders including cancer. Hence, understanding the Hh signaling mechanisms, as proposed by this project, may provide new avenues for improving diagnosis and therapeutics of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061269-13
Application #
8484407
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2000-03-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$311,397
Indirect Cost
$115,550
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
Tian, Aiguo; Shi, Qing; Jiang, Alice et al. (2015) Injury-stimulated Hedgehog signaling promotes regenerative proliferation of Drosophila intestinal stem cells. J Cell Biol 208:807-19
Tian, Aiguo; Jiang, Jin (2015) Hedgehog fuels gut regeneration. Oncotarget 6:20750-1
Zhou, Zizhang; Yao, Xia; Li, Shuang et al. (2015) Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling. Dev Cell 34:58-72
Li, S; Jiang, C; Pan, J et al. (2015) Regulation of c-Myc protein stability by proteasome activator REGγ. Cell Death Differ 22:1000-11
Han, Yuhong; Shi, Qing; Jiang, Jin (2015) Multisite interaction with Sufu regulates Ci/Gli activity through distinct mechanisms in Hh signal transduction. Proc Natl Acad Sci U S A 112:6383-8
Li, Qi; Li, Shuangxi; Mana-Capelli, Sebastian et al. (2014) The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell 31:291-304
Jiang, Kai; Liu, Yajuan; Fan, Junkai et al. (2014) Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila. Proc Natl Acad Sci U S A 111:E4842-50
Tian, Aiguo; Jiang, Jin (2014) Intestinal epithelium-derived BMP controls stem cell self-renewal in Drosophila adult midgut. Elife 3:e01857
Li, Shuang; Ma, Guoqiang; Wang, Bing et al. (2014) Hedgehog induces formation of PKA-Smoothened complexes to promote Smoothened phosphorylation and pathway activation. Sci Signal 7:ra62

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