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The Hedgehog Pathway Effector Smoothened Exhibits Signaling Competency in the Absence of Ciliary Accumulation

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

Chem Biol. 2014 Dec 18;21(12):1680-9.

PMID: 25484239

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP548779608	IHR-1		548779-60-8	Price

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