The TAK1-NLK-MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF
The TAK1-NLK-MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF
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DOI：
10.1038/21674
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发表时间：
1999-06-24
期刊：
影响因子：
64.8
通讯作者：
Matsumoto, K
中科院分区：
文献类型：
--
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
Wnt信号通路通过β-连环蛋白和T细胞因子/淋巴增强因子(TCF/LEF)家族的高迁移率族转录因子(1-5)的复合体调控许多发育过程。WNT稳定胞浆中的β-连环蛋白，然后与TCF结合并激活基因转录。这种信号级联在脊椎动物、果蝇和秀丽线虫中是保守的。在线虫中，MoM-4和LIT-I蛋白调节Wnt信号，使胚胎发育期间的反应细胞极化(6)。MOM-4和LIT-1在哺乳动物细胞中分别与TAK1(一种由转化生长因子-β激活的激酶)、丝裂原激活的蛋白激酶-激酶(MAP3K)(7)和MAPK(MAPK)相关的NEMO-like激酶(NLK)(8、9)同源。这些结果增加了TAK1和NLK也参与哺乳动物细胞Wnt信号转导的可能性。在这里，我们表明，TAK1激活刺激NLK活性，并下调由β-连环蛋白和TCF介导的转录激活。注射NLK可抑制显微注射β-连环素对非洲爪哇胚胎轴复制的诱导作用。NLK使TCF/LEF因子磷酸化，并抑制β-连环蛋白-TCF复合体与DNA的相互作用。因此，TAK1-NLK-MAPK样通路对Wnt信号通路起负性调节作用。
The Wnt signalling pathway regulates many developmental processes through a complex of beta-catenin and the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of high-mobility-group transcription factors(1-5). Wnt stabilizes cytosolic beta-catenin, which then binds to TCF and activates gene transcription. This signalling cascade is conserved in vertebrates, Drosophila and Caenorhabditis elegans. In C. elegans, the proteins MOM-4 and LIT-I regulate Wnt signalling to polarize responding cells during embryogenesis(6). MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-beta) mitogen-activated protein-kinase-kinase kinase (MAP3K)(7) and MAP kinase (MAPK)-related NEMO-like kinase (NLK)(8,9), respectively, in mammalian cells. These results raise the possibility that TAK1 and NLK are also involved in Wnt signalling in mammalian cells. Here we show that TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. Injection of NLK suppresses the induction of axis duplication by microinjected beta-catenin in Xenopus embryos. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin-TCF complex with DNA. Thus, the TAK1-NLK-MAPK-like pathway negatively regulates the Wnt signalling pathway.