Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C
Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C
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DOI：
10.1002/j.1460-2075.1996.tb00830.x
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发表时间：
1996-09-02
期刊：
影响因子：
11.4
通讯作者：
Dale, TC
中科院分区：
文献类型：
--
作者：
Cook, D;Fry, MJ;Dale, TC
果蝇基因产物Wingless（Wg）是一种分泌型糖蛋白，属于Wnt基因家族成员。对果蝇表皮发育的遗传分析表明，Zw 3/sgg（zeste-white 3/shaggy）基因产物参与了Wg的旁分泌信号通路。通过遗传分析已经鉴定了Wnt-（和通过推断Wnt-）介导的信号传导途径，大多数因子的生物化学意义仍未得到证实，在这里，我们表明在小鼠10 T1/2成纤维细胞中，糖原合成酶激酶-3（GSK-3）（Zw 3/Sgg的鼠同源物）的活性被Wg灭活，这通过与胰岛素介导的GSK-3调节不同的信号传导途径发生，因为Wg向GSK-3的信号传导对渥曼青霉素不敏感。WG诱导的GSK-3失活对蛋白激酶C（PKC）抑制剂Ro 31 -8220和用佛波酯延长的10 T1/2成纤维细胞预处理都敏感。这些研究结果提供了第一个生化证据，支持从Wg到Zw 3/Sgg的遗传定义的途径，并表明在Wnt/Wg信号转导过程中GSK-3/Zw 3上游的PKC先前未表征的作用。
The Drosophila gene product Wingless (Wg) is a secreted glycoprotein and a member of the Wnt gene family, Genetic analysis of Drosophila epidermal development has defined a putative paracrine Wg signalling pathway involving the zeste-white 3/shaggy (zw3/sgg) gene product, Although putative components of Wg- (and by inference Wnt-) mediated signalling pathways have been identified by genetic analysis, the biochemical significance of most factors remains unproven, Here we show that in mouse 10T1/2 fibroblasts the activity of glycogen synthase kinase-3 (GSK-3), the murine homologue of Zw3/Sgg, is inactivated by Wg, This occurs through a signalling pathway that is distinct from insulin-mediated regulation of GSK-3 in that Wg signalling to GSK-3 is insensitive to wortmannin, Additionally, Wg-induced inactivation of GSK-3 is sensitive to both the protein kinase C (PKC) inhibitor Ro31-8220 and prolonged pre-treatment of 10T1/2 fibroblasts with phorbol ester. These findings provide the first biochemical evidence in support of the genetically defined pathway from Wg to Zw3/Sgg, and suggest a previously uncharacterized role for a PKC upstream of GSK-3/Zw3 during Wnt/Wg signal transduction.