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Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling

While Wnt-Frizzled (Fzd) signaling is critical in the pathophysiology of carcinomas, its role in human breast cancer has been difficult to establish. We show here that the adaptor protein Na(+)/H(+) Exchange Regulatory Factor1 (NHERF1), a protein abundantly expressed in normal mammary epithelium, re...

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Autores principales: Wheeler, David S., Barrick, Stacey R., Grubisha, Melanie J., Brufsky, Adam M., Friedman, Peter A., Romero, Guillermo
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995822/
https://www.ncbi.nlm.nih.gov/pubmed/20802536
http://dx.doi.org/10.1038/onc.2010.389
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author Wheeler, David S.
Barrick, Stacey R.
Grubisha, Melanie J.
Brufsky, Adam M.
Friedman, Peter A.
Romero, Guillermo
author_facet Wheeler, David S.
Barrick, Stacey R.
Grubisha, Melanie J.
Brufsky, Adam M.
Friedman, Peter A.
Romero, Guillermo
author_sort Wheeler, David S.
collection PubMed
description While Wnt-Frizzled (Fzd) signaling is critical in the pathophysiology of carcinomas, its role in human breast cancer has been difficult to establish. We show here that the adaptor protein Na(+)/H(+) Exchange Regulatory Factor1 (NHERF1), a protein abundantly expressed in normal mammary epithelium, regulates Wnt signaling, maintaining low levels of β-catenin activation. NHERF1’s effects are mediated by direct interactions between one of its PSD-95/Drosophila discs large/ZO-1 domains (PDZ domains) and the C-terminus of a subset of Fzd receptors. Loss of NHERF1 in breast cancer cell lines enhances canonical Wnt signaling and Wnt-dependent cell proliferation. Furthermore, the mammary glands of NHERF1 knockout mice exhibit increased mammary duct density accompanied by increased proliferation and β-catenin activity. Finally, we demonstrate a negative correlation between NHERF1 expression and nuclear β-catenin in human breast carcinomas. Taken together, these results provide novel insight into the regulation of Wnt signaling in normal and neoplastic breast tissues, and identify NHERF1 as an important regulator of the pathogenesis of breast tumors.
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spelling pubmed-29958222011-07-06 Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling Wheeler, David S. Barrick, Stacey R. Grubisha, Melanie J. Brufsky, Adam M. Friedman, Peter A. Romero, Guillermo Oncogene Article While Wnt-Frizzled (Fzd) signaling is critical in the pathophysiology of carcinomas, its role in human breast cancer has been difficult to establish. We show here that the adaptor protein Na(+)/H(+) Exchange Regulatory Factor1 (NHERF1), a protein abundantly expressed in normal mammary epithelium, regulates Wnt signaling, maintaining low levels of β-catenin activation. NHERF1’s effects are mediated by direct interactions between one of its PSD-95/Drosophila discs large/ZO-1 domains (PDZ domains) and the C-terminus of a subset of Fzd receptors. Loss of NHERF1 in breast cancer cell lines enhances canonical Wnt signaling and Wnt-dependent cell proliferation. Furthermore, the mammary glands of NHERF1 knockout mice exhibit increased mammary duct density accompanied by increased proliferation and β-catenin activity. Finally, we demonstrate a negative correlation between NHERF1 expression and nuclear β-catenin in human breast carcinomas. Taken together, these results provide novel insight into the regulation of Wnt signaling in normal and neoplastic breast tissues, and identify NHERF1 as an important regulator of the pathogenesis of breast tumors. 2010-08-30 2011-01-06 /pmc/articles/PMC2995822/ /pubmed/20802536 http://dx.doi.org/10.1038/onc.2010.389 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wheeler, David S.
Barrick, Stacey R.
Grubisha, Melanie J.
Brufsky, Adam M.
Friedman, Peter A.
Romero, Guillermo
Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling
title Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling
title_full Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling
title_fullStr Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling
title_full_unstemmed Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling
title_short Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling
title_sort direct interaction between nherf1 and frizzled regulates β-catenin signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995822/
https://www.ncbi.nlm.nih.gov/pubmed/20802536
http://dx.doi.org/10.1038/onc.2010.389
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