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Oxysterols are allosteric activators of the oncoprotein Smoothened

Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which plays 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 protei...

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Detalles Bibliográficos
Autores principales: Nachtergaele, Sigrid, Mydock, Laurel K., Krishnan, Kathiresan, Rammohan, Jayan, Schlesinger, Paul H., Covey, Douglas F., Rohatgi, Rajat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262054/
https://www.ncbi.nlm.nih.gov/pubmed/22231273
http://dx.doi.org/10.1038/nchembio.765
Descripción
Sumario:Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which plays 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 their function through a specific protein target. We present several lines of evidence that this protein target is the 7-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 their mechanism of action.