The hedgehog pathway effector smoothened exhibits signaling competency in the absence of ciliary accumulation

Chih Wei Fan, Baozhi Chen, Irene Franco, Jianming Lu, Heping Shi, Shuguang Wei, Changguang Wang, Xiaofeng Wu, Wei Tang, Michael G. Roth, Noelle S. Williams, Emilio Hirsch, Chuo Chen, Lawrence Lum

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Summary Misactivation of the seven-transmembrane protein Smoothened (Smo) is frequently associated with basal cell carcinoma and medulloblastoma. Cellular exposure to secreted Hedgehog (Hh) protein or oncogenic mutations in Hh pathway components induces Smo accumulation in the primary cilium, an antenna-like organelle with mostly unknown cellular functions. Despite the data supporting an indispensable role of the primary cilium in Smo activation, the mechanistic underpinnings of this dependency remain unclear. Using a cell-membrane-impermeable Smo antagonist (IHR-1), we demonstrate that Smo supplied with a synthetic agonist or activated with oncogenic mutations can signal without ciliary accumulation. Similarly, cells with compromised ciliary Smo trafficking due to loss of the phosphatidylinositol-4-phosphate 3-kinase (PI3K)-C2α retain transcriptional response to an exogenously supplied Smo agonist. These observations suggest that assembly of a Smo-signaling complex in the primary cilium is not a prerequisite for Hh pathway activation driven by Smo agonists or oncogenic Smo molecules.

Original languageEnglish (US)
Pages (from-to)1680-1689
Number of pages10
JournalChemistry and Biology
Volume21
Issue number12
DOIs
StatePublished - Dec 18 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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