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  • Original Article
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Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3β-mediated phosphorylation of β-catenin

Oncogene volume 27, pages 274–284 (2008)Cite this article

Abstract

The Wnt signaling pathway is essential for embryonic development and carcinogenesis. Upon Wnt stimulation, β-catenin is stabilized and associates with T-cell factor or lymphoid enhancing factor, thereby activating transcription of target genes. In the absence of Wnt stimulation, the level of β-catenin is reduced via glycogen synthase kinase (GSK)-3β-mediated phosphorylation and subsequent proteasome-dependent degradation. Here, we report the identification of Ajuba as a negative regulator of the Wnt signaling pathway. Ajuba is a member of LIM domain-containing proteins that contribute to cell fate determination and regulate cell proliferation and differentiation. We found that enforced expression of Ajuba destabilized β-catenin and suppressed target gene expression. Ajuba promoted GSK-3β-mediated phosphorylation of β-catenin by reinforcing the association between β-catenin and GSK-3β. Furthermore, Wnt stimulation induced both accumulation of β-catenin and destabilization of Ajuba. Our findings suggest that Ajuba is important for regulation of the Wnt signaling pathway.

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Abbreviations

APC:

adenomatous polyposis coli

GFP:

green fluorescent protein

GSK-3β:

glycogen synthase kinase-3β

GST:

glutathione S-transferase

HA:

hemagglutinin

LEF:

lymphoid enhancing factor

PBS:

phosphate-buffered saline

TCF:

T-cell factor

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Acknowledgements

We thank T Nakamura for β-catenin plasmids, A Kikuchi for GSK-3β plasmids and T Kitamura for Plat-E cells. We also thank N Tokai-Nishizumi, T Suzuki, K Yokoyama and M Delawary for experimental suggestions. This work was supported by grants-in-aid from the Japan Society for the Promotion of Science and from the Ministry of Education, Cultures, Sports, Science and Technology, Japan.

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  1. Y Abe

    Present address: 4Current address: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki 211-8533, Japan.,

Authors and Affiliations

  1. Division of Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    K Haraguchi, M Ohsugi, Y Abe & T Yamamoto

  2. Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    K Semba

  3. Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Bioscience, University of Tokyo, Tokyo, Japan

    T Akiyama

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  1. K Haraguchi
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Correspondence to T Yamamoto.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Haraguchi, K., Ohsugi, M., Abe, Y. et al. Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3β-mediated phosphorylation of β-catenin. Oncogene 27, 274–284 (2008). https://doi.org/10.1038/sj.onc.1210644

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