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
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DOI：
10.1016/j.chembiol.2014.10.013
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发表时间：
2014-12-18
影响因子：
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通讯作者：
Lum, Lawrence
中科院分区：
文献类型：
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作者：
Fan, Chih-Wei;Chen, Baozhi;Lum, Lawrence
七跨膜蛋白Smoothened（Smo）的误激活经常与基底细胞癌和髓母细胞瘤有关。细胞暴露于分泌的Hedgehog（Hh）蛋白或Hh通路组分中的致癌突变诱导Smo在初级纤毛中积累，初级纤毛是一种具有大多数未知细胞功能的触角样细胞器。尽管有数据支持初级纤毛在Smo激活中不可或缺的作用，但这种依赖性的机制基础仍不清楚。使用细胞膜不可渗透的Smo拮抗剂（IHR-1），我们证明，Smo提供了一个合成的激动剂或激活致癌突变可以无纤毛积累的信号。类似地，由于磷脂酰肌醇-4-磷酸3-激酶（PI 3 K）-C2 α的损失而具有受损的纤毛Smo运输的细胞保留对外源提供的Smo激动剂的转录应答。这些观察结果表明，在初级纤毛中的Smo信号传导复合物的组装不是由Smo激动剂或致癌Smo分子驱动的Hh通路激活的先决条件。
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)-C2 alpha 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.