Genentech, South San Francisco, CA 94080, USA.
Mol Cell Biol. 2010 Apr;30(8):1910-22. doi: 10.1128/MCB.01089-09. Epub 2010 Feb 12.
Hedgehog (Hh) signaling in vertebrates depends on intraflagellar transport (IFT) within primary cilia. The Hh receptor Patched is found in cilia in the absence of Hh and is replaced by the signal transducer Smoothened within an hour of Hh stimulation. By generating antibodies capable of detecting endogenous pathway transcription factors Gli2 and Gli3, we monitored their kinetics of accumulation in cilia upon Hh stimulation. Localization occurs within minutes of Hh addition, making it the fastest reported readout of pathway activity, which permits more precise temporal and spatial localization of Hh signaling events. We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. We also confirmed that phosphorylation and betaTrCP/Cul1 are required for endogenous Gli3 processing and that this is inhibited by Hh. Surprisingly, however, Hh-dependent inhibition of processing does not lead to accumulation of full-length Gli3, but instead renders it labile, leading to its proteasomal degradation via the SPOP/Cul3 complex. In fact, full-length Gli3 disappears with faster kinetics than the Gli3 repressor, the latter not requiring SPOP/Cul3 or betaTrCP/Cul1. This may contribute to the increased Gli3 activator/repressor ratios found in IFT mutants.
脊椎动物中的刺猬 (Hh) 信号依赖于初级纤毛内的鞭毛内运输 (IFT)。在 Hh 刺激的一个小时内,Hh 受体 Patched 存在于纤毛中,而信号转导 Smoothened 取代了它。通过生成能够检测内源性途径转录因子 Gli2 和 Gli3 的抗体,我们监测了它们在 Hh 刺激后在纤毛中的积累动力学。定位发生在 Hh 添加后的几分钟内,使其成为报道的最快的途径活性读出,这允许更精确的时空定位 Hh 信号事件。我们表明,在纤毛尖端积累的 Gli3 物种是全长的,并且可能不是蛋白激酶 A 磷酸化的。我们还证实了磷酸化和 betaTrCP/Cul1 是内源性 Gli3 加工所必需的,并且 Hh 抑制了这种加工。然而,令人惊讶的是,Hh 依赖性加工抑制不会导致全长 Gli3 的积累,而是使其不稳定,通过 SPOP/Cul3 复合物导致其蛋白酶体降解。事实上,全长 Gli3 的消失速度比 Gli3 抑制剂更快,后者不需要 SPOP/Cul3 或 betaTrCP/Cul1。这可能有助于解释在 IFT 突变体中发现的增加的 Gli3 激活物/抑制剂比率。
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