Oxysterols are allosteric activators of the oncoprotein Smoothened
Open accessAbstract
Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S)-hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. We present several lines of evidence that this protein target is the seven-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing sterol signaling mechanisms.
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Downstream factors that mediate SMO-dependent activation of GLI2 are varied and include G proteins and other proteins such as the EVC2 complex.
“Downstream factors that mediate SMO-dependent activation of GLI2 are varied, and include G proteins and other proteins such as the EVC2 complex 104, 115.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [115]
The Abstract says Smo activity allows Gli transcription factors to initiate target-gene transcription, but it does not identify mediators of GLI2 activation. The Discussion says that coupling to distinct downstream signaling complexes remains to be determined. Searches for EVC2 and G proteins as downstream mediators found no passage supporting the attributed examples. (LLM, conf=0.72)
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Self-citation
- Authors
- Nachtergaele, S., Mydock, L. K., Krishnan, K., Rammohan, J., Schlesinger, P. H., Covey, D. F., & Rohatgi, R.
- Affiliations
- Stanford Medicine (US)
- Washington University in St. Louis (US)
- Venue
- Nature Chemical Biology
- Published
- 2012-01-08
- Volume
- 8
- Issue
- 2
- Pages
- 211-220
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3262054
- OpenAlex
- W2085775776
- Cited by
- 284
- References
- 49
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 8 · 2023: 21 · 2022: 17 · 2021: 15 · 2020: 19 · 2019: 23 · 2018: 22 · 2017: 17 · 2016: 21 · 2015: 26 · 2014: 32 · 2013: 31 · 2012: 15
- FWCI
- 13.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p60dk020579-35, 5p41rr000954-34)
- National Heart, Lung, and Blood Institute (R01HL067773, T32HL007275)
- National Cancer Institute (R00CA129174)
- National Institute of General Medical Sciences (P01GM047969, T32GM007276)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK-020579, P30DK056341, P30DK020579)
- National Center for Research Resources (P41-RR000954)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- oxysterols, Smoothened, Hedgehog signaling, allosteric activation, stereoselectivity, enantiomers, epimers
- MeSH terms
- Smoothened Receptor, Allosteric Regulation, Humans, Hydroxycholesterols, Ligands, Sterols, Signal Transduction, Oncogene Proteins, Receptors, G-Protein-Coupled, Hedgehog Proteins
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