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

  • Chem Biol. 2014 Dec 18;21(12):1680-9. doi: 10.1016/j.chembiol.2014.10.013.
Chih-Wei Fan  1 ,  Baozhi Chen  1 ,  Irene Franco  2 ,  Jianming Lu  3 ,  Heping Shi  3 ,  Shuguang Wei  3 ,  Changguang Wang  3 ,  Xiaofeng Wu  1 ,  Wei Tang  1 ,  Michael G Roth  3 ,  Noelle S Williams  3 ,  Emilio Hirsch  2 ,  Chuo Chen  3 ,  Lawrence Lum  4
Affiliations
  • 1. Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
  • 2. Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
  • 3. Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
  • 4. Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 25484239 DOI: 10.1016/j.chembiol.2014.10.013
Abstract

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.

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