Hedgehog-Stimulated Chemotaxis Is Mediated by Smoothened Located Outside the Primary Cilium
Hedgehog-Stimulated Chemotaxis Is Mediated by Smoothened Located Outside the Primary Cilium
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DOI：
10.1126/scisignal.2002798
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发表时间：
2012-08-21
影响因子：
7.3
通讯作者：
Roelink, Henk
中科院分区：
文献类型：
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作者：
Bijlsma, Maarten F.;Damhofer, Helene;Roelink, Henk
Hedgehog (Hh) 通路的调节依赖于两个受体的相互作用。在 Hh 缺失的情况下，Patched1 (Ptch1) 会抑制该通路。配体 Hh 与 Ptch1 的结合刺激激活受体 Smoothened (Smo) 定位到初级纤毛，这是转录 Hh 反应所必需的。 Hh 还可以通过非转录途径诱导趋化性。我们评估了 Smo 纤毛定位缺陷对其亚细胞运输和介导趋化信号传导能力的影响。表达不能定位于初级纤毛的 Smo 突变体的细胞或缺乏初级纤毛的细胞显示出 Smo 的细胞内运输改变，并且响应 Hh 或 Smo 激动剂，减少转录信号传导并增强趋化反应性。因此，纤毛定位机制似乎将 Smo 转运至可介导转录信号传导的亚细胞位点，并远离可介导趋化信号传导的位置。因此，Smo 的亚细胞定位是其信号传导特征的关键决定因素，并且意味着存在专门用于趋化性的 Smo 池。
Regulation of the Hedgehog (Hh) pathway relies on an interaction of two receptors. In the absence of Hh, Patched1 (Ptch1) inhibits the pathway. Binding of the ligand Hh to Ptch1 stimulates the localization of the activating receptor Smoothened (Smo) to the primary cilium, which is required for the transcriptional Hh response. Hh can also induce chemotaxis through a nontranscriptional pathway. We assessed the effects of defective ciliary localization of Smo on its subcellular trafficking and ability to mediate chemotactic signaling. Cells expressing mutants of Smo that could not localize to the primary cilium or cells lacking the primary cilium showed altered intracellular trafficking of Smo and, in response to Hh or Smo agonists, decreased transcriptional signaling and enhanced chemotactic responsiveness. Thus, the ciliary localization machinery appears to transport Smo to subcellular sites where it can mediate transcriptional signaling and away from locations where it can mediate chemotactic signaling. The subcellular localization of Smo is thus a crucial determinant of its signaling characteristics and implies the existence of a pool of Smo dedicated to chemotaxis.