Inhibition of Hedgehog Signaling by Direct Binding of Cyclopamine to Smoothened

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2002 Nov 5

PMID 12414725

Citations 608

Authors

James K Chen

Jussi Taipale

Michael K Cooper

Philip A Beachy

Affiliations

Soon will be listed here.

Abstract

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.

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