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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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References

  • Brembeck FH, Schwarz-Romond T, Bakkers J, Wilhelm S, Hammerschmidt M, Birchmeier W . (2004). Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions. Genes Dev 18: 2225–2230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YT, Stewart DB, Nelson WJ . (1999). Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells. J Cell Biol 144: 687–699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai JL, Wang L, Sahin AA, Broemeling LD, Schutte M, Pan Y . (2004). NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer. Oncogene 23: 8681–8687.

    Article  PubMed  Google Scholar 

  • Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H . (1999). The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci USA 96: 10182–10187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giles RH, van Es JH, Clevers H . (2003). Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653: 1–24.

    CAS  PubMed  Google Scholar 

  • Gottardi CJ, Gumbiner BM . (2004). Distinct molecular forms of beta-catenin are targeted to adhesive or transcriptional complexes. J Cell Biol 167: 339–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCrea PD, Gumbiner BM . (1991). Purification of a 92-kDa cytoplasmic protein tightly associated with the cell-cell adhesion molecule E-cadherin (uvomorulin). Characterization and extractability of the protein complex from the cell cytostructure. J Biol Chem 266: 4514–4520.

    CAS  PubMed  Google Scholar 

  • Morales FC, Takahashi Y, Kreimann EL, Georgescu M-M . (2004). Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc Natl Acad Sci USA 101: 17705–17710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nelson WJ, Nusse R . (2004). Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303: 1483–1487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Provost E, Rimm DL . (1999). Controversies at the cytoplasmic face of the cadherin-based adhesion complex. Curr Opin Cell Biol 11: 567–572.

    Article  CAS  PubMed  Google Scholar 

  • Reczek D, Berryman M, Bretscher A . (1997). Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J Cell Biol 139: 169–179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reynolds AB, Daniel J, McCrea PD, Wheelock MJ, Wu J, Zhang Z . (1994). Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol 14: 8333–8342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sadot E, Simcha I, Shtutman M, Ben-Ze'ev A, Geiger B . (1998). Inhibition of beta-catenin-mediated transactivation by cadherin derivatives. Proc Natl Acad Sci USA 95: 15339–15344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shenolikar S, Voltz JW, Cunningham R, Weinman EJ . (2004). Regulation of ion transport by the NHERF family of PDZ proteins. Physiology (Bethesda) 19: 362–369.

    CAS  Google Scholar 

  • Shibata T, Chuma M, Kokubu A, Sakamoto M, Hirohashi S . (2003). EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. Hepatology 38: 178–186.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki J, Sukezane T, Akagi T, Georgescu MM, Ohtani M, Inoue H et al. (2004). Loss of c-abl facilitates anchorage-independent growth of p53- and RB-deficient primary mouse embryonic fibroblasts. Oncogene 23: 8527–8534.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi Y, Morales FC, Kreimann EL, Georgescu MM . (2006). PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling. EMBO J 25: 910–920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeichi M . (1995). Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7: 619–627.

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP . (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    Article  CAS  PubMed  Google Scholar 

  • Voltz JW, Weinman EJ, Shenolikar S . (2001). Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation. Oncogene 20: 6309–6314.

    Article  CAS  PubMed  Google Scholar 

  • Weinman EJ, Wang Y, Wang F, Greer C, Steplock D, Shenolikar S . (2003). A C-terminal PDZ motif in NHE3 binds NHERF-1 and enhances cAMP inhibition of sodium-hydrogen exchange. Biochemistry 42: 12662–12668.

    Article  CAS  PubMed  Google Scholar 

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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

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  1. E L Kreimann
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  2. F C Morales
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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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