# Understanding WNT9A/FZD9 Trafficking and Signaling

> **NIH NIH R35** · VAN ANDEL RESEARCH INSTITUTE · 2022 · $250,000

## Abstract

Cell to cell signaling is fundamental to all multicellular life. Secreted signaling molecules from one cell are
able to communicate with other cells through interaction with receptors on the surface, which interpret and
transduce these signals. One such class of secreted signaling molecules is encoded by the Wnt gene family.
These protein products drive a plethora of cellular processes, including cellular symmetry, proliferation, tissue
polarity and stem cell maintenance. This variety of processes occurs using conserved intracellular machinery to
program these outputs, indicating a need for complex control at the level of the cell membrane. At least part of
the regulation of this signaling complexity lies in the multiple genes encoding specific ligands (19 in mammals)
and receptors (10 in mammals). However, the specific mechanisms that start with the association of
various ligands and receptors at the membrane, and lead to nuclear transcriptional activity are
incompletely understood. One of the missing links in this aspect is to decipher how the receptor complex is
internalized by the cell, where it is trafficked to, and how these events lead to diverse transcriptional outputs.
This system of ligand-receptor inputs leading to diverse outputs is likely dependent on the composition of the
receptor complex, and the cellular context of the signal. Deciphering this code will be crucial to our understanding
of how cells receive and transduce specific signals. This proposal aims to characterize the communication
between trafficking of a specific Wnt signaling receptor complex, and activation of transcription in the nucleus.
 Although it is known that pairing a Wnt ligand and Frizzled (Fzd) receptor is required for the transduction of
many (if not most) Wnt signals, our understanding of the mechanisms through which specific Wnt/Fzd pairings
allow the transcriptional activator β-catenin (β-cat) to enter the nucleus is lacking. We have developed a novel
system to study specific signal transduction of this nature by fluorescently labeled the Wnt ligand, Fzd receptor,
and the transcriptional activator β-cat. This is based on our previous studies which have indicated that there is
an exquisitely specific pairing of the ligand Wnt9a with the receptor Frizzled (Fzd)9b, and that specificity
of this signal is conferred by the epidermal growth factor receptor (EGFR). This proposal aims to further
define the mechanism of Wnt9a/Fzd9b signal transduction by studying the intracellular trafficking of this receptor
complex, and coupling this to β-cat movements. By first understanding how one specific Wnt/Fzd pairing
establishes a specific signal, we can generate a model for further testing other Wnt/Fzd complexes in different
cellular contexts. Furthermore, cell signaling events often cross-over to other pathways; these findings could
certainly impact our understanding of how other receptor-ligand complexes lead to diverse outputs in cells.
 The PI has expertise in Wnt ...

## Key facts

- **NIH application ID:** 10680985
- **Project number:** 3R35GM142779-02S1
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Stephanie Laura Grainger
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $250,000
- **Award type:** 3
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680985

## Citation

> US National Institutes of Health, RePORTER application 10680985, Understanding WNT9A/FZD9 Trafficking and Signaling (3R35GM142779-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10680985. Licensed CC0.

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