Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened

The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct bindin...

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Bibliographic Details
Published in:Genes & development 2002-11, Vol.16 (21), p.2743-2748
Main Authors: Chen, James K, Taipale, Jussi, Cooper, Michael K, Beachy, Philip A
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Binding Sites
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - physiology
Hedgehog Proteins
Mice
Protein Binding
Protein Conformation
Receptors, Cell Surface - chemistry
Receptors, Cell Surface - drug effects
Receptors, Cell Surface - physiology
Receptors, G-Protein-Coupled
Research Communication
Signal Transduction - drug effects
Smoothened Receptor
Teratogens - pharmacology
Teratogens - toxicity
Trans-Activators - physiology
Veratrum Alkaloids - chemistry
Veratrum Alkaloids - pharmacology
Veratrum Alkaloids - toxicity
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Summary:The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo). Cyclopamine also can reverse the retention of partially misfolded Smo in the endoplasmic reticulum, presumably through binding-mediated effects on protein conformation. These observations reveal the mechanism of cyclopamine's teratogenic and antitumor activities and further suggest a role for small molecules in the physiological regulation of Smo.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1025302