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

被引：216

作者：

Rohatgi, Rajat ^{[1
,2
,3
,4
]}

Milenkovic, Ljiljana ^{[1
,2
,3
]}

Corcoran, Ryan B. ^{[1
,2
,3
]}

Scott, Matthew P. ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA

[2] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Genet, Stanford, CA 94305 USA

[3] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Bioengn, Stanford, CA 94305 USA

[4] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Oncol, Stanford, CA 94305 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 09期

关键词：

developmental signaling; Hedgehog inhibitor; primary cilium; transport; PRIMARY CILIUM; INTRAFLAGELLAR TRANSPORT; CYCLOPAMINE; INHIBITION; MUTATIONS; RECEPTOR; BINDING;

D O I：

10.1073/pnas.0813373106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：3196 / 3201

页数：6

共 22 条

[1] Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened [J].