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Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function

Oncogene volume 26, pages 5290–5299 (2007)Cite this article

Abstract

Anchorage-independent growth is a hallmark of tumor growth and results from enhanced proliferation and altered cell–cell and cell-matrix interactions. By using gene-deficient mouse embryonic fibroblasts (MEFs), we showed for the first time that NHERF1/EBP50 (Na/H exchanger regulator factor 1/ezrin-radixin-moesin binding phosphoprotein 50), an adapter protein with membrane localization under physiological conditions, inhibits cell motility and is required to suppress anchorage-independent growth. Both NHERF1 PDZ domains are necessary for the tumor suppressor effect. NHERF1 associates directly through the PDZ2 domain with β-catenin and is required for β-catenin localization at the cell–cell junctions in MEFs. Mechanistically, the absence of NHERF1 selectively decreased the interaction of β-catenin with E-cadherin, but not with N-cadherin. The ensuing disorganization of E-cadherin-mediated adherens junctions as well as the observed moderate increase in β-catenin transcriptional activity contributed most likely to the anchorage-independent growth of NHERF1-deficient MEFs. In vivo, NHERF1 is specifically localized at the apical brush-border membrane in intestinal epithelial cells and is required to maintain a fraction of the cortical β-catenin at this level. Thus, NHERF1 emerges as a cofactor essential for the integrity of epithelial tissues by maintaining the proper localization and complex assembly of β-catenin.

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Acknowledgements

MMG acknowledges support from MD Anderson Cancer Center Tobacco Fund and NCI-CA107201, FCM from American Brain Tumor Association and ELK from NCI-CA09299-26. NCI-CA16672 partially supported animal breeding.

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Authors and Affiliations

  1. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    E L Kreimann, F C Morales, J de Orbeta-Cruz, Y Takahashi, T-J Liu & M-M Georgescu

  2. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Adams & M-M Georgescu

  3. Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P D McCrea

Authors
  1. E L Kreimann
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  2. F C Morales
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  3. J de Orbeta-Cruz
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  4. Y Takahashi
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  5. H Adams
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  6. T-J Liu
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  7. P D McCrea
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  8. M-M Georgescu
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Corresponding author

Correspondence to M-M Georgescu.

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

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Kreimann, E., Morales, F., de Orbeta-Cruz, J. et al. Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function. Oncogene 26, 5290–5299 (2007). https://doi.org/10.1038/sj.onc.1210336

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  • DOI: https://doi.org/10.1038/sj.onc.1210336

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