Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction
Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction
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DOI：
10.1038/ncb1210
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发表时间：
2005-01-01
影响因子：
21.3
通讯作者：
Tomlinson, A
中科院分区：
文献类型：
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作者：
Apionishev, S;Katanayeva, NM;Tomlinson, A
刺猬（HH）信号通路对于动物发育至关重要，并且在几种类型的癌症中被异常激活（1）。在果蝇中，HH信号传导通过转录因子Cubitus Intruptus（CI）调节靶基因表达。蛋白激酶A，酪蛋白激酶1和糖原合酶激酶3在没有配体的情况下通过在定义的一组位点磷酸化CI在没有配体的情况下静音，从而促进其蛋白水解转化为转录抑制剂（CI-3）（CI-3）（2,3）（2,3 ）。在HH存在的情况下，CI-155不再转换为CI-75，其激活转录的能力被增强。所有HH响应都需要七个跨膜结构域蛋白平滑（1,4），在HH信号传导过程中，它们本身变为过度磷酸化（5）。在这里，我们表明，一组蛋白激酶A和蛋白激酶A-pred酪蛋白激酶1磷酸化位点在平滑状态，类似地分布到调节CI的磷酸化位点，对于平滑以传递HH信号和正常调节平滑蛋白质水平是必不可少的。
The Hedgehog (Hh) signalling pathway is crucial for animal development and is aberrantly activated in several types of cancer(1). In Drosophila melanogaster, Hh signalling regulates target gene expression through the transcription factor Cubitus interruptus (Ci). Together, Protein Kinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 silence the pathway in the absence of ligand by phosphorylating Ci at a defined cluster of sites, thereby promoting its proteolytic conversion to a transcriptional repressor (Ci-75)(2,3). In the presence of Hh, Ci-155 is no longer converted to Ci-75 and its ability to activate transcription is potentiated. All Hh responses require the seven transmembrane domain protein Smoothened(1,4), which itself becomes hyperphosphorylated during Hh signalling(5). Here we show that a cluster of protein kinase A and protein kinase A-primed casein kinase 1 phosphorylation sites in Smoothened, similarly distributed to those regulating Ci, are essential for Smoothened to transduce a Hh signal and for normal regulation of Smoothened protein levels.