Oxysterols reveal novel Smoothened regulatory mechanisms in vertebrate Hedgehog signaling
Abstract/Contents
- Abstract
- The Hedgehog pathway is a highly conserved signaling cascade that coordinates embryonic development. Loss of function and aberrant activation of Hedgehog signaling have also been implicated in a variety of pathologies. The membrane protein Smoothened is a central signal transducer in this pathway, but how it is regulated is a longstanding mystery. It has been proposed that Smoothened has an endogenous small molecule ligand that could be regulated by the upstream regulator, Patched. Oxysterols are a class of endogenous cholesterol metabolites that can activate Hedgehog signaling, but their mechanism of action was a mystery. I focused on 20(S)-hydroxycholesterol (20(S)-OHC), the most potent activator out of the panel of oxysterols initially tested. Through pharmacological and biochemical analysis, I found that oxysterols target Smoothened through a site that is distinct from the one most other Smoothened drugs occupy. I went on to map the oxysterol binding site to the extracellular Smoothened cysteine rich domain (CRD). These studies revealed that the Smoothened CRD represents a crucial regulatory module of Smoothened in the context of endogenous signaling through Patched. Through the work presented here, I developed novel chemical tools that have allowed me to identify the mechanism by which oxysterols activate Hedgehog signaling through Smoothened. Most importantly, however, this work has revealed a conserved role for the Smoothened CRD in the regulation of Hedgehog signaling. It remains to be determined whether the Smoothened CRD directly receives a signal from Patched, or whether it plays a more indirect role in regulating signaling levels. Understanding this has important implications for the broader question of how Smoothened is regulated by Patched.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Nachtergaele, Sigrid |
|---|---|
| Associated with | Stanford University, Department of Biochemistry. |
| Primary advisor | Rohatgi, Rajat |
| Thesis advisor | Rohatgi, Rajat |
| Thesis advisor | Harbury, Pehr |
| Thesis advisor | Pfeffer, Suzanne |
| Advisor | Harbury, Pehr |
| Advisor | Pfeffer, Suzanne |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Sigrid Nachtergaele. |
|---|---|
| Note | Submitted to the Department of Biochemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Sigrid Hilde Martine Nachtergaele
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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