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Molecular and Cellular Biology, January 2003, p. 131-139, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.131-139.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The TAK1-NLK Mitogen-Activated Protein Kinase Cascade Functions in the Wnt-5a/Ca²⁺ Pathway To Antagonize Wnt/ß-Catenin Signaling

Department of Molecular Biology, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602,¹ Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444,² Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045,³ Department of Molecular Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan,⁵ Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, California 92697-4025,⁴ Howard Hughes Medical Institute, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, Washington 98195-7350⁶

Received 12 June 2002/ Returned for modification 5 August 2002/ Accepted 8 October 2002

Wnt signaling controls a variety of developmental processes. The canonical Wnt/ß-catenin pathway functions to stabilize ß-catenin, and the noncanonical Wnt/Ca²⁺ pathway activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). In addition, the Wnt/Ca²⁺ pathway activated by Wnt-5a antagonizes the Wnt/ß-catenin pathway via an unknown mechanism. The mitogen-activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and NLK MAPK also negatively regulates the canonical Wnt/ß-catenin signaling pathway. Here we show that activation of CaMKII induces stimulation of the TAK1-NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1. Furthermore, by using a chimeric receptor (ß₂AR-Rfz-2) containing the ligand-binding and transmembrane segments from the ß₂-adrenergic receptor (ß₂AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation with the ß-adrenergic agonist isoproterenol activates activities of endogenous CaMKII, TAK1, and NLK and inhibits ß-catenin-induced transcriptional activation. These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca²⁺ pathway and antagonizes canonical Wnt/ß-catenin signaling.

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