# Sending and receiving Hedgehog and Wnt signals

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $439,733

## Abstract

Project summary
 The Hedgehog (Hh) and Wnt signaling pathways are essential for embryogenesis, adult stem cell
maintenance, and are deeply involved in cancer and birth defects. Both pathways are activated by lipid-
modified secreted ligands: Hh ligands are modified with palmitate and cholesterol, while Wnt ligands are
modified with palmitate. Lipidation is essential for the function of Hh and Wnt ligands, but it makes them stick
strongly to membranes, raising the question of how they spread from producing cells.
 We discovered that Hh is released from cells by forming a stable complex with a dedicated carrier
protein, Scube, a process catalyzed by the membrane transporter Dispatched, which uses the energy of the
plasma membrane sodium gradient. Scube then delivers Hh to its receptor, the tumor suppressor membrane
protein Patched, triggering specific cellular responses. We found that, surprisingly, Scube blocks binding of Hh
to Patched, raising the question of how the Scube-Hh complex activates signaling. We discovered that three
cell surface proteins Cdon, Boc and Gas1, known as co-receptors for Hh, are essential for signaling by Scube-
Hh. Specifically, we showed that the Hh co-receptors define a novel sequential pathway whereby Cdon and
Boc recruit Scube-Hh to the cell surface, after which Gas1 catalyzes Hh transfer from Scube to Patched. We
also used cryo-electron microscopy to determine the structure of Dispatched-Hh and Gas1-Hh-Patched
complexes, which capture Hh in the process of release and delivery, respectively. Finally, we discovered two
families of secreted proteins that function as carriers for Wnts, explaining how Wnts are released in soluble
and active form.
 Our findings open several critical questions about Hh and Wnt signaling. We propose combining
biochemistry, structural, chemical and cell biology to accomplish the following aims:
1) To determine how Dispatched and Scube cooperate to release Hh ligands
2) To elucidate how Gas1 catalyzes formation of the Hh-Patched complex, to trigger Hh signaling
3) To elucidate how Wnt ligands are secreted and then delivered to responding cells
 These studies are important for the following reasons: A) They will advance understanding of the Hh
and Wnt pathways, by elucidating critical pathways controlling the ligands; B) They will identify novel targets for
blocking signaling in cancer, based on the mechanisms of Hh and Wnt ligand release and delivery; and C) Our
novel chemical probes will be broadly applicable to study cholesterol and fatty acids in health and in disease.

## Key facts

- **NIH application ID:** 10440069
- **Project number:** 2R01GM122920-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** ADRIAN SALIC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $439,733
- **Award type:** 2
- **Project period:** 2018-05-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440069

## Citation

> US National Institutes of Health, RePORTER application 10440069, Sending and receiving Hedgehog and Wnt signals (2R01GM122920-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10440069. Licensed CC0.

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