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
Liu, Chen; Zhou, Zizhang; Yao, Xia et al. (2014) Hedgehog signaling downregulates suppressor of fused through the HIB/SPOP-Crn axis in Drosophila. Cell Res 24:595-609
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
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
Shi, Qing; Han, Yuhong; Jiang, Jin (2014) Suppressor of fused impedes Ci/Gli nuclear import by opposing Trn/Kap?2 in Hedgehog signaling. J Cell Sci 127:1092-103
Ren, Fangfang; Shi, Qing; Chen, Yongbin et al. (2013) Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration. Cell Res 23:1133-46
Chen, Yongbin; Jiang, Jin (2013) Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res 23:186-200
Yue, Tao; Tian, Aiguo; Jiang, Jin (2012) The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Dev Cell 22:255-67
Wang, Yuxiao; He, Huawei; Srivastava, Nishi et al. (2012) Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci Signal 5:ra6
Li, Shuang; Chen, Yongbin; Shi, Qing et al. (2012) Hedgehog-regulated ubiquitination controls smoothened trafficking and cell surface expression in Drosophila. PLoS Biol 10:e1001239
Amcheslavsky, Alla; Ito, Naoto; Jiang, Jin et al. (2011) Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol 193:695-710

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