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Nuclear GSK-3β inhibits the canonical Wnt signalling pathway in a β-catenin phosphorylation-independent manner

Oncogene volume 27, pages 3546–3555 (2008)Cite this article

Abstract

β-Catenin is the central signalling molecule of the canonical Wnt pathway, where it activates target genes in a complex with lymphoid enhancer factor/T-cell factor transcription factors in the nucleus. The regulation of β-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3β (GSK-3β) that phosphorylates β-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3β has a nuclear function in downregulating the activity of β-catenin. Using colorectal cell lines that express a mutant form of β-catenin, which cannot be phosphorylated by GSK-3β and ectopically expressed mutant β-catenin protein, we show that nuclear GSK-3β functions in a mechanism that does not involve β-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3β enters the nucleus, forms a complex with β-catenin and lowers the levels of β-catenin/TCF-dependent transcription in a mechanism that involves GSK-3β–Axin binding.

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Abbreviations

CRC:

colorectal cancer

GSK-3β:

glycogen synthase kinase-3β

TCF/LEF:

T-cell factor/lymphoid enhancer factor

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Acknowledgements

We thank Dr Avri Ben-Ze'ev of the Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, and Dr Arnona Gazit of the Department of Human Microbiology, Tel Aviv University for critical reading of the manuscript. This work was supported by grants from The Israel Science Foundation (ISF), the ISRAEL CANCER RESEARCH FUND (ICRF) and the Israel Cancer Association.

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  1. M Caspi and A Zilberberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Anthropology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    M Caspi, A Zilberberg & R Rosin-Arbesfeld

  2. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    H Eldar-Finkelman

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  1. M Caspi
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  2. A Zilberberg
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Correspondence to R Rosin-Arbesfeld.

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

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Caspi, M., Zilberberg, A., Eldar-Finkelman, H. et al. Nuclear GSK-3β inhibits the canonical Wnt signalling pathway in a β-catenin phosphorylation-independent manner. Oncogene 27, 3546–3555 (2008). https://doi.org/10.1038/sj.onc.1211026

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