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

Nature volume 399, pages 798–802 (1999)Cite this article

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.

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Figure 1: Effect of TAK1 and NLK on β-catenin–TCF-regulated transcription.
Figure 2: Effects of NLK on axis formation.
Figure 3: Kinase activity of NLK.
Figure 4: Interaction between TCF/LEF and the TAK1-NLK pathway.
Figure 5: Effect of NLK on a β-catenin–TCF-4 complex.
Figure 6: Model for interaction between the Wnt and TAK1/MOM-4–NLK/LIT-1 pathways.

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Acknowledgements

We thank T. Akiyama, B. Brott, and A. Kikuchi for materials; E. Nishida for helpful discussions; and M. Lamphier and R. Ruggieri for critical reading of the manuscript. Supported by special grants for CREST and Advanced Research on Cancer from the Ministry of Education, Culture and Science of Japan, and HFSP (K.M.).

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Authors and Affiliations

  1. Department of Molecular Biology, Graduate School of Science, Nagoya University,

    Tohru Ishitani, Jun Ninomiya-Tsuji & Kunihiro Matsumoto

  2. CREST, Japan Science and Technology Corporation, Chikusa-ku, 464-8602, Nagoya, Japan

    Tohru Ishitani, Jun Ninomiya-Tsuji & Kunihiro Matsumoto

  3. Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, Okazaki, 444-8585, Japan

    Shin-ichi Nagai, Michiru Nishita & Hiroshi Shibuya

  4. The Institute of Molecular Biology, The University of Oregon, 1370 Franklin Blvd., Eugene, Oregon, 97403, USA

    Marc Meneghini & Bruce Bowerman

  5. Department of Immunology, University Hospital, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Nick Barker & Hans Clevers

  6. Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, 92697-4025, California, USA

    Marian Waterman

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Correspondence to Kunihiro Matsumoto.

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Ishitani, T., Ninomiya-Tsuji, J., Nagai, Si. et al. The TAK1–NLK–MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF. Nature 399, 798–802 (1999). https://doi.org/10.1038/21674

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