# Hedgehog Signaling in Development and Metabolism

> **NIH NIH R35** · UNIVERSITY OF KENTUCKY · 2020 · $382,500

## Abstract

Abstract:
Hedgehog (Hh) signaling plays critical roles in pattern formation and cell growth control and is also involved in
metabolic control. Further, aberrant Hh signaling causes diverse types of cancers. Transduction of the Hh
signal requires the G protein-coupled receptor (GPCR) family protein Smoothened (Smo) in both insects and
mammals. While many components in the Hh pathway have been identified, how the Hh signal is transduced
through the 12-span transmembrane protein Patched (Ptc) to Smo is still unclear. This team has discovered 1)
that Smo undergoes phosphorylation by multiple kinases, which leads to Smo cell surface accumulation and
signaling activity; 2) that sumoylation induced by Hh promotes Smo activation; and 3) that ubiquitination
downregulates Smo cell surface accumulation by promoting Smo endocytosis. Results from these studies
suggest that, in response to Hh stimulation, multiple steps occur in Smo regulation. However, despite
significant progress, key questions persist regarding the mechanism controlling Smo protein expression and
activation: 1) How is Smo transcription specifically regulated? 2) Whether and how does Hh regulate lipolysis?
3) How does cholesterol activate Smo? and 4) Whether and how is the sodium pump involved in Ptc and Smo
regulation? Recent discoveries by this group that Smo transcription is specifically regulated in adipose tissue,
that an alternative cholesterol biosynthesis pathway regulates Smo accumulation and activation, and that the
sodium pump plays a positive role in activating Smo, likely by regulating cholesterol on the plasma membrane
are critical foundations to answering those questions. The overarching goal of this research program is to
understand how Hh signals are sensed and transmitted to control downstream biological events that ultimately
govern cell growth and patterning. Drosophila fat body and oenocyte have emerged as attractive models to
study lipid metabolism and circulation. Published and preliminary findings in these models have indicated that
lipid accumulation is regulated by highly conserved signaling pathways, and that Hh signaling controls not only
lipogenesis but also lipolysis by regulating specific genes. These studies provide new tools and hypotheses for
investigating the mechanisms of Smo signaling and the role of Hh/Smo signaling in regulating lipid metabolism,
which particular relevance to such cancers as basal cell carcinoma and medulloblastoma. The proposed five-
year program of studies uses a combination of genetic and biochemical approaches to build on prior
contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study will
provide novel insights into mechanisms surrounding Smo suppression by Ptc and activation by cholesterol. In
addition, expected outcomes will provide novel insights into human developmental disorders and promote
development of diagnostic tools and novel therapeutic approaches to oppose Smo drug resis...

## Key facts

- **NIH application ID:** 10000958
- **Project number:** 5R35GM131807-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Jianhang Jia
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000958

## Citation

> US National Institutes of Health, RePORTER application 10000958, Hedgehog Signaling in Development and Metabolism (5R35GM131807-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000958. Licensed CC0.

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