Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.

By James K. Chen, Jussi Taipale, M. K. Cooper, P. Beachy. Genes & Development, 2002

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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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5bebe85d015bf0a67039dfc120ee2b9b4083daf0

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Citations in the corpus

Hedgehog signalling in cancer formation and maintenance (2003, background): “More importantly, inhibition of HH signalling via treatment with cyclopamine — a naturally occurring cholesterol analogue that inhibits SMO and functions through interaction with the HEPTAHELICAL BUNDLE”
Mechanisms and functions of Hedgehog signalling across the metazoa (2011, background): “This is supported by the finding that the steroidal alkaloid cyclopamine binds to and inhibits SMO activit”
Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network (2008, background): “Use of small-molecule antagonists and Smo agonists in neural cells indicate that a graded activation of Smo recapitulates the graded cellular response to a Shh concentration gradient (Chen et al., 2002a; Chen et al., 2002b; Dessaud et al., 2007; Frank- Kamenetsky et al., 2002).”
Communicating with Hedgehogs (2005, background): “Various cyclopamine mimics (and other small molecules) bind to the transmembrane helices of SMO and either activate or inhibit signallin”
Basal cell carcinomas: attack of the hedgehog (2008, background): “Cyclopamine is a competitive inhibitor of SMO signalling, binding directly to the protei”
Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. (2006, neutral): “300 nmol/L cyclopamine (18) in our studies.”
Tissue repair and stem cell renewal in carcinogenesis (2004, result): “Consistent with this possibility, recent studies using cyclopamine, a specific Hh pathway antagonis”
Drosophila orthologues to human disease genes: an update on progress. (2008, background): “Cyclopamine, a compound in the corn lily, Veratrum californicum, was found to act as an inhibitor of smoothened and, as a consequence, suppressor of hedgehog signaling (81, 82).”
The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. (2003, positive): “The reorienting effect is blocked by cycloan underestimate of the true loss-of-Smo phenotype. pamine, indicating a requirement for Smo in mediating this effect (Chen et al., 2002; Frank-Kamenetsky et al., (A–”
Hedgehog: functions and mechanisms. (2008, background): “2006) based on its ability to compete against binding of labeled cyclopamine (Chen et al. 2002a).”
Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours (2003, background): “Pathway activation, whether triggered by Hh binding or by PTCH mutation, requires SMO, a seven-transmembrane protein that binds to and is inactivated by the pathway antagonist cyclopamin”
Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer (2003, background): “through interaction with the Hh signalling protein smoothene”
HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. (2007, positive): “All but one adherent primary cultures of gliomas tested decreased cell proliferation as measured by BrdU incorporation after 48h treatment with cyclopamine, a specific SMOH inhibitor (10), as compared with tomatidine as control (Fig.”