Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process

doi:10.1073/pnas.0813373106

Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process

Departments of ^aDevelopmental Biology,
^bGenetics,
^cBioengineering, and
^dOncology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305

Contributed by Matthew P. Scott, December 31, 2008
↵¹R.R. and L.M. contributed equally to this work. (received for review November 10, 2008)

Abstract

The Hedgehog (Hh) signaling pathway controls growth, cell fate decisions, and morphogenesis during development. Damage to Hh transduction machinery can lead to birth defects and cancer. The transmembrane protein Smoothened (Smo) relays the Hh signal and is an important drug target in cancer. Smo enrichment in primary cilia is thought to drive activation of target genes. Using small-molecule agonists and antagonists to dissect Smo function, we find that Smo enrichment in cilia is not sufficient for signaling and a distinct second step is required for full activation. This 2-step mechanism—localization followed by activation—has direct implications for the design and use of anticancer therapeutics targeted against Smo.

Keywords:

Footnotes

²To whom correspondence should be addressed. E-mail: mscott{at}stanford.edu
Author contributions: R.R., L.M., R.B.C., and M.P.S. designed research; R.R., L.M., and R.B.C. performed research; R.R. and L.M. contributed new reagents/analytic tools; R.R., L.M., R.B.C., and M.P.S. analyzed data; and R.R., L.M., and M.P.S. wrote the paper.
The authors declare no conflict of interest.
↵* LoRusso PM, et al. (2008) A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors. American Society for Clinical Oncology Annual Meeting, May 30–June 3, 2008, Chicago, IL, abstr 3516.
This article contains supporting information online at www.pnas.org/cgi/content/full/0813373106/DCSupplemental.
Freely available online through the PNAS open access option.