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Nuclear-cytoplasmic shuttling of APC regulates β-catenin subcellular localization and turnover

Nature Cell Biology volume 2, pages 653–660 (2000)Cite this article

Abstract

Mutational inactivation of the APC gene is a key early event in the development of familial adenomatous polyposis and colon cancer. APC suppresses tumour progression by promoting degradation of the oncogenic transcriptional activator β-catenin. APC gene mutations can lead to abnormally high levels of β-catenin in the nucleus, and the consequent activation of transforming genes. Here, we show that APC is a nuclear-cytoplasmic shuttling protein, and that it can function as a β-catenin chaperone. APC contains two active nuclear export sequences (NES) at the amino terminus, and mutagenesis of these conserved motifs blocks nuclear export dependent on the CRM1 export receptor. Treatment of cells with the CRM1-specific export inhibitor leptomycin B shifts APC from cytoplasm to nucleus. β-catenin localization is also regulated by CRM1, but in an APC-dependent manner. Transient expression of wild-type APC in SW480 (APCmut/mut) colon cancer cells enhances nuclear export and degradation of β-catenin, and these effects can be blocked by mutagenesis of the APC NES. These findings suggest that wild-type APC controls the nuclear accumulation of β-catenin by a combination of nuclear export and cytoplasmic degradation.

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Figure 1: Nuclear-cytoplasmic shuttling of APC.
Figure 2: Identification of APC nuclear export signals.
Figure 3: Site-directed NES mutations block APC nuclear export.
Figure 4: β-catenin accumulates in the nucleus when nuclear export is blocked.
Figure 5: APC(1–1,309) can export β-catenin from the nucleus.
Figure 6: Co-localization of wild-type APC and β-catenin in SW480 cells.
Figure 7: CRM1 regulates APC-dependent degradation of β-catenin.
Figure 8: Model for APC-mediated nuclear export of β-catenin.

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Acknowledgements

I thank B. Vogelstein, K. Kinzler and T. Dale for supplying plasmids, and M. Yoshida for leptomycin B. I am grateful to A. Eleftheriou and M. Galea for help with plasmid construction, and to J. Rodriguez and H. Rizos for comments on the manuscript. This research was supported in part by grants from the NSW Cancer Council, the Leo & Jenny Cancer Foundation, and the National Health and Medical Research Council of Australia.

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  1. Westmead Institute for Cancer Research, University of Sydney, Westmead Millenium Institute, Westmead, 2145, NSW , Australia

    Beric R. Henderson

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Henderson, B. Nuclear-cytoplasmic shuttling of APC regulates β-catenin subcellular localization and turnover. Nat Cell Biol 2, 653–660 (2000). https://doi.org/10.1038/35023605

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