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Molecular and Cellular Biology, February 2003, p. 1379-1389, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1379-1389.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Lymphoid Enhancer Factor 1/T-Cell Factor by Mitogen-Activated Protein Kinase-Related Nemo-Like Kinase-Dependent Phosphorylation in Wnt/ß-Catenin Signaling

Tohru Ishitani, Jun Ninomiya-Tsuji, and Kunihiro Matsumoto*

Department of Molecular Biology, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602, Japan

Received 21 October 2002/ Returned for modification 14 November 2002/ Accepted 21 November 2002

The Wnt/ß-catenin signaling pathway regulates many developmental processes by modulating gene expression. Wnt signaling induces the stabilization of cytosolic ß-catenin, which then associates with lymphoid enhancer factor and T-cell factor (LEF-1/TCF) to form a transcription complex that activates Wnt target genes. Previously, we have shown that a specific mitogen-activated protein (MAP) kinase pathway involving the MAP kinase kinase kinase TAK1 and MAP kinase-related Nemo-like kinase (NLK) suppresses Wnt signaling. In this study, we investigated the relationships among NLK, ß-catenin, and LEF-1/TCF. We found that NLK interacts directly with LEF-1/TCF and indirectly with ß-catenin via LEF-1/TCF to form a complex. NLK phosphorylates LEF-1/TCF on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced LEF-1 transcriptional activity and rendered it resistant to inhibition by NLK. Phosphorylation of TCF-4 by NLK inhibited DNA binding by the ß-catenin-TCF-4 complex. However, this inhibition was abrogated when a mutant form of TCF-4 was used in which both threonines were replaced with valines. These results suggest that NLK phosphorylation on these sites contributes to the down-regulation of LEF-1/TCF transcriptional activity.

* Corresponding author. Mailing address: Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Phone: 81-52-789-3000. Fax: 81-52-789-2589 or -3001. E-mail: g44177a{at}nucc.cc.nagoya-u.ac.jp.

Molecular and Cellular Biology, February 2003, p. 1379-1389, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1379-1389.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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