# Maximizing Investigators' Research Award (R35 - Clinical Trial Optional)

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2022 · $562,675

## Abstract

PROJECT SUMMARY:
The evolutionarily conserved Wnt pathway plays a critical role during metazoan development
and stem cell maintenance in the adult. Mutations in the Wnt pathway leading to its
misregulation in humans have been shown to contributes to both developmental defects and
cancers. In the latter case, over 90% of all non-hereditary forms of colorectal cancers are
initiated by mutations in the Wnt pathway leading to its inappropriate activation. There are no
FDA-approved drugs that inhibit the Wnt pathway, which is likely due to our incomplete
understanding of the mechanism of Wnt signaling and the lack of suitable drug targets. The
primary focus of my lab is to understand the biological function of the Wnt signaling pathway by
deciphering its molecular mechanism and identifying new Wnt components. Our ultimate goal is
to use this information to understand how deregulation of the Wnt pathway can lead to Wnt-
driven diseases in humans.
Over more than a decade, my lab has made significant contributions to our fundamental
understanding of Wnt signaling. These breakthroughs were accomplished via the development
of the first biochemical system (using Xenopus egg extract), the reconstitution of active purified
proteins, the development of the first mathematical model (Lee-Heinrich model), and the
identification of small molecule inhibitors (CK1 agonists), one of which has been designated by
the FDA as an orphan drug for a familial precancerous disease (familial adenomatous
polyposis).
Our current work focused on determining the role of the USP46/UAF1/WDR20 deubiquitinase
complex in regulating LRP6 receptor turnover, the mechanism by which APC regulates Wnt
receptor activity, the role of the -catenin degradation complex in mediating bistable pathway
behavior, and the roles of USP47 and STK38, in regulating Wnt signaling. In our renewal
application, we now propose to 1) reconstitute LRP6 ubiquitylation and identify its evolutionarily
conserved E3 ligase, 2) understand the basis for signal compensation upon Wnt receptor loss in
APC mutant cells, 3) provide evidence for the role of bistability in generating morphogenetic
signaling, and 4) uncover the roles of the STK38 and TRIP12 in nuclear Wnt signaling.

## Key facts

- **NIH application ID:** 10402163
- **Project number:** 2R35GM122516-06
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** ETHAN LEE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $562,675
- **Award type:** 2
- **Project period:** 2017-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402163

## Citation

> US National Institutes of Health, RePORTER application 10402163, Maximizing Investigators' Research Award (R35 - Clinical Trial Optional) (2R35GM122516-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10402163. Licensed CC0.

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