Jia Jianhang, Amanai Kazuhito, Wang Gelin, Tang Jiong, Wang Bing, Jiang Jin
Center for Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
Nature. 2002 Apr 4;416(6880):548-52. doi: 10.1038/nature733. Epub 2002 Mar 24.
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. 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), 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.
果蝇蛋白“蓬乱”（Sgg，也称为“小体-白色3”，Zw3）及其脊椎动物同源物糖原合酶激酶3（GSK3）是无翅（Wg）和Wnt信号通路的抑制性成分。在此我们表明，Sgg也是刺猬索尼克（Hh）信号通路中的负调控因子。在果蝇中，Hh发挥作用的方式有两种，一种是阻止全长的间断翅脉（Ci，Ci155）进行蛋白水解加工，从而产生截短的阻遏物形式（Ci75），另一种是刺激积累的Ci155的活性（参考文献2 - 6）。sgg基因功能的丧失导致细胞自主积累高水平的Ci155，并导致包括果蝇转化生长因子β（dpp）和无翅（wg）在内的Hh反应基因的异位表达。同时去除sgg和融合抑制因子（Su(fu)）会导致翅膀重复，类似于异位Hh信号传导所引起的情况。Ci在被蛋白激酶A（PKA）进行引发磷酸化后会被GSK3磷酸化，而突变Ci中的GSK3磷酸化位点会阻止其加工过程，并防止阻遏物形式的产生。我们提出，Sgg/GSK3与PKA共同作用导致Ci的过度磷酸化，使其成为蛋白水解加工的靶点，而Hh通过促进Ci的去磷酸化来对抗Ci的蛋白水解。
