The TAK1-NLK-MAPK-related pathway antagonizes signalling between β- catenin and transcription factor TCF

Tohru Ishitani, Jun Ninomiya-Tsuji, Shln Ichl Nagai, Michiru Nishita, Marc Meneghini, Nick Barker, Marian Waterman, Bruce Bowerman, Hans Clevers, Hiroshi Shibuya, Kunihiro Matsumoto

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Abstract

The Wnt signalling pathway regulates many developmental processes through a complex of β-catenin and the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of high-mobility-group transcription factors. Wnt stabilizes cytosolic β-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-1 regulate Wnt signalling to polarize responding cells during embryogenesis. MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-β) mitogen-activated protein-kinase-kinase kinase (MAP3K) and MAP kinase (MAPK)-related NEMO-like kinase (NLK), 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 β-catenin and TCF. Injection of NLK suppresses the induction of axis duplication by microinjected β-catenin in Xenopus embryos. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the β- catenin-TCF complex with DNA. Thus, the TAK1-NLK-MAPK-like pathway negatively regulates the Wnt signalling pathway.

Original languageEnglish
Pages (from-to)798-802
Number of pages5
JournalNature
Volume399
Issue number6738
DOIs
Publication statusPublished - Jun 24 1999

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Cite this

Ishitani, T., Ninomiya-Tsuji, J., Nagai, S. I., Nishita, M., Meneghini, M., Barker, N., ... Matsumoto, K. (1999). The TAK1-NLK-MAPK-related pathway antagonizes signalling between β- catenin and transcription factor TCF. Nature, 399(6738), 798-802. https://doi.org/10.1038/21674