The Hedgehog Pathway Effector Smoothened Exhibits Signaling Competency in the Absence of Ciliary Accumulation
| Autor: | Shuguang Wei, Chuo Chen, Emilio Hirsch, Chih Wei Fan, Wei Tang, Baozhi Chen, Chang-Guang Wang, Lawrence G. Lum, Irene Franco, Noelle S. Williams, Jianming Lu, Michael G. Roth, Xiaofeng Wu, Heping Shi |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Agonist medicine.drug_class Clinical Biochemistry Biology Biochemistry Protein Structure Secondary Article Cell Line Receptors G-Protein-Coupled Drug Discovery medicine Animals Humans Hedgehog Proteins Cilia Molecular Biology Hedgehog PI3K/AKT/mTOR pathway Pharmacology Effector Cilium General Medicine Hedgehog signaling pathway Cell biology Protein Structure Tertiary Cancer research Molecular Medicine Signal transduction Smoothened Signal Transduction |
| Zdroj: | Chemistry & Biology. 21:1680-1689 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2014.10.013 |
| Popis: | SummaryMisactivation 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. |
| Databáze: | OpenAIRE |
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