# Sending and receiving Hedgehog signals

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $381,375

## Abstract

Project summary
 The Hedgehog cell-cell signaling pathway is essential for embryonic development, for adult stem cell
maintenance, and is deeply involved in human cancer and birth defects. The pathway is activated by the
Hedgehog ligand, a secreted protein uniquely modified with two lipids, which are both essential for function: a
fatty acid and cholesterol. From the producing cell, the Hedgehog ligand spreads to distant cells, on the
surface of which it binds its receptor, a tumor suppressor membrane protein called Patched, thus triggering a
specific set of cellular responses. A puzzling aspect of the Hedgehog ligand is that it spreads and signals at a
distance, in spite of the fact that its lipid modifications make it stick strongly to membranes. Many critical
aspects of the Hedgehog ligand remain obscure: we do not know how it is released from cells, how it is able to
diffuse outside the cell, and how it is delivered to responding cells.
 We recently discovered that Hedgehog ligand release is accomplished by two synergistic interactions
involving its cholesterol modification: one with the membrane protein Dispatched, and the second with the
secreted protein Scube. Using novel chemical probes, we found that Dispatched and Scube recognize
cholesterol differently, suggesting that the Hedgehog ligand is handed off from Dispatched to Scube. We also
discovered that Scube is important for ligand reception, via Cdon and Boc, two proteins critical for Hedgehog
signaling; this suggested a novel mechanism for Hedgehog ligand delivery. Finally, we found that Gas1,
another protein important for Hedgehog ligand reception, interacts with the ligand in a unique way, dependent
on its fatty acid modification; this indicated that Gas1 uses a mechanism distinct from Cdon and Boc.
 We propose to use a combination of biochemistry, cell biology, and chemical biology to accomplish the
following aims:
A) To elucidate precisely how the Hedgehog ligand is released form the membrane of producing cells
B) To determine how Scube delivers the Hedgehog ligand to responding cells via Cdon and Boc
C) To elucidate how Gas1 participates in Hedgehog ligand reception
 These studies are important to undertake for the following reasons: 1) They will advance our
understanding of the Hedgehog pathway, by elucidating the route taken by the Hedgehog ligand during the
signaling process; 2) They will identify novel targets for blocking Hedgehog signaling in cancer, based on the
mechanisms of Hedgehog ligand release and delivery; and 3) Our novel chemical probes will be broadly
applicable to study cholesterol and fatty acids in health and in disease.

## Key facts

- **NIH application ID:** 9879751
- **Project number:** 5R01GM122920-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** ADRIAN SALIC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,375
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879751

## Citation

> US National Institutes of Health, RePORTER application 9879751, Sending and receiving Hedgehog signals (5R01GM122920-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9879751. Licensed CC0.

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