A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes.
A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes.
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DOI：
10.1083/jcb.201004108
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发表时间：
2010-10-18
期刊：
影响因子：
--
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Tukachinsky H;Lopez LV;Salic A
通过睫状膜蛋白Smoothened的Hedgehog信号传导使Gli转录因子与其抑制剂融合抑制因子解离。在脊椎动物中，Hedgehog（Hh）信号在初级纤毛中启动，激活膜蛋白Smoothened（Smo），并导致Gli蛋白的激活，Gli蛋白是该途径的转录效应物。在没有信号传导的情况下，Gli蛋白被胞质蛋白融合抑制因子（SuFu）抑制。目前尚不清楚Hh如何激活Gli以及它是否直接调节SuFu。我们发现，Hh刺激迅速招募内源性SuFu-Gli复合物纤毛，这表明一个模型中，Smo激活Gli通过解除抑制SuFu。为了支持这一模型，我们发现Hh引起SuFu-Gli复合物的快速解离，从而允许Gli进入细胞核并激活转录。蛋白激酶A（PKA）（Hh信号传导的抑制剂）的活化阻断SuFu-Gli复合物的纤毛定位，这反过来防止它们通过信号传导解离。我们的研究结果支持一个简单的机制，在脊椎动物纤毛Hh信号引起的非活性SuFu-Gli复合物的解离，PKA抑制的过程。
Hedgehog signaling through the ciliary membrane protein Smoothened dissociates the Gli transcription factors from their inhibitor, Suppressor of Fused. In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu–Gli complexes to cilia, suggesting a model in which Smo activates Gli by relieving inhibition by SuFu. In support of this model, we find that Hh causes rapid dissociation of the SuFu–Gli complex, thus allowing Gli to enter the nucleus and activate transcription. Activation of protein kinase A (PKA), an inhibitor of Hh signaling, blocks ciliary localization of SuFu–Gli complexes, which in turn prevents their dissociation by signaling. Our results support a simple mechanism in which Hh signals at vertebrate cilia cause dissociation of inactive SuFu–Gli complexes, a process inhibited by PKA.
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