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

Tohru Ishitani, Jun Ninomiya-Tsuji, Shin-ichi Nagai, Michiru Nishita, Marc Meneghini, Nick Barker, Marian Waterman, Bruce Bowerman, Hans Clevers, Hiroshi Shibuya and Kunihiro Matsumoto ()
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Tohru Ishitani: Graduate School of Science, Nagoya University
Jun Ninomiya-Tsuji: Graduate School of Science, Nagoya University
Shin-ichi Nagai: National Institute for Basic Biology
Michiru Nishita: National Institute for Basic Biology
Marc Meneghini: The Institute of Molecular Biology, The University of Oregon
Nick Barker: University Hospital
Marian Waterman: College of Medicine, University of California
Bruce Bowerman: The Institute of Molecular Biology, The University of Oregon
Hans Clevers: University Hospital
Hiroshi Shibuya: National Institute for Basic Biology
Kunihiro Matsumoto: Graduate School of Science, Nagoya University

Nature, 1999, vol. 399, issue 6738, 798-802

Abstract: 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 factors1,2,3,4,5,. 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 embryogenesis6. MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-β) 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 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.

Date: 1999
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DOI: 10.1038/21674

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