Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus
Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus
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DOI：
10.1038/nature733
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发表时间：
2002-04-04
期刊：
影响因子：
64.8
通讯作者：
Jiang, J
中科院分区：
文献类型：
--
作者：
Jia, JH;Amanal, K;Jiang, J
果蝇蛋白 Shaggy（Sgg，也称为 Zeste-white3、Zw3）及其脊椎动物直系同源糖原合酶激酶 3 (GSK3) 是 Wingless (Wg) 和 Wnt 通路的抑制成分 (1)。在这里，我们表明 Sgg 也是 Hedgehog (Hh) 通路中的负调节因子。在果蝇中，Hh 通过阻断全长 Cubitus Interruptus Ci (Ci155) 的蛋白水解加工来产生截短的阻遏蛋白形式 (Ci75)，并通过刺激累积的 Ci155 的活性来发挥作用（参考文献 2-6）。 sgg 基因功能的丧失会导致细胞自主积累高水平的 Ci155 和 Hh 反应基因（包括十肢瘫痪 (dpp) 和 wg）的异位表达。同时去除 sgg 和融合抑制子 Su(fu)(7)，会导致类似于异位 Hh 信号传导引起的翼重复。 Ci 在被蛋白激酶 A (PKA) 引发磷酸化后被 GSK3 磷酸化，Ci 中 GSK3 磷酸化位点的突变会阻止其加工并阻止阻遏物形式的产生。我们提出，Sgg/GSK3 与 PKA 联合作用，引起 Ci 的过度磷酸化，从而靶向 Ci 进行蛋白水解加工，而 Hh 通过促进 Ci 的去磷酸化来对抗 Ci 的蛋白水解。
The Drosophila protein Shaggy (Sgg, also known as Zeste-white3, Zw3) and its vertebrate orthologue glycogen synthase kinase 3 (GSK3) are inhibitory components of the Wingless (Wg) and Wnt pathways(1). Here we show that Sgg is also a negative regulator in the Hedgehog (Hh) pathway. In Drosophila, Hh acts both by blocking the proteolytic processing of full-length Cubitus interruptus, Ci (Ci155), to generate a truncated repressor form( Ci75), and by stimulating the activity of accumulated Ci155 (refs 2-6). Loss of sgg gene function results in a cell-autonomous accumulation of high levels of Ci155 and the ectopic expression of Hh-responsive genes including decapentaplegic (dpp) and wg. Simultaneous removal of sgg and Suppressor of fused, Su(fu)(7), results in wing duplications similar to those caused by ectopic Hh signalling. Ci is phosphorylated by GSK3 after a primed phosphorylation by protein kinase A (PKA), and mutating GSK3-phosphorylation sites in Ci blocks its processing and prevents the production of the repressor form. We propose that Sgg/GSK3 acts in conjunction with PKA to cause hyperphosphorylation of Ci, which targets it for proteolytic processing, and that Hh opposes Ci proteolysis by promoting its dephosphorylation.