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The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone

In the lactating breast, ERBB4 localizes to the nuclei of secretory epithelium while regulating activities of the signal transducer and activator of transcription (STAT) 5A transcription factor essential for milk-gene expression. We have identified an intrinsic ERBB4 NLS (residues 676–684) within th...

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Autores principales: Williams, Christopher C., Allison, June G., Vidal, Gregory A., Burow, Matthew E., Beckman, Barbara S., Marrero, Luis, Jones, Frank E.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172499/
https://www.ncbi.nlm.nih.gov/pubmed/15534001
http://dx.doi.org/10.1083/jcb.200403155
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author Williams, Christopher C.
Allison, June G.
Vidal, Gregory A.
Burow, Matthew E.
Beckman, Barbara S.
Marrero, Luis
Jones, Frank E.
author_facet Williams, Christopher C.
Allison, June G.
Vidal, Gregory A.
Burow, Matthew E.
Beckman, Barbara S.
Marrero, Luis
Jones, Frank E.
author_sort Williams, Christopher C.
collection PubMed
description In the lactating breast, ERBB4 localizes to the nuclei of secretory epithelium while regulating activities of the signal transducer and activator of transcription (STAT) 5A transcription factor essential for milk-gene expression. We have identified an intrinsic ERBB4 NLS (residues 676–684) within the ERBB4 intracellular domain (4ICD) that is essential for nuclear accumulation of 4ICD. To determine the functional significance of 4ICD nuclear translocation in a physiologically relevant system, we have demonstrated that cotransfection of ERBB4 and STAT5A in a human breast cancer cell line stimulates β-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the β-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin β1 (HRG)-stimulated cells and both proteins bind to the endogenous β-casein promoter in T47D breast cancer cells. Together, our results establish a novel molecular mechanism of transmembrane receptor signal transduction involving nuclear cotranslocation of the receptor intracellular domain and associated transcription factor. Subsequent binding of the two proteins at transcription factor target promoters results in activation of gene expression.
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spelling pubmed-21724992008-03-05 The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone Williams, Christopher C. Allison, June G. Vidal, Gregory A. Burow, Matthew E. Beckman, Barbara S. Marrero, Luis Jones, Frank E. J Cell Biol Research Articles In the lactating breast, ERBB4 localizes to the nuclei of secretory epithelium while regulating activities of the signal transducer and activator of transcription (STAT) 5A transcription factor essential for milk-gene expression. We have identified an intrinsic ERBB4 NLS (residues 676–684) within the ERBB4 intracellular domain (4ICD) that is essential for nuclear accumulation of 4ICD. To determine the functional significance of 4ICD nuclear translocation in a physiologically relevant system, we have demonstrated that cotransfection of ERBB4 and STAT5A in a human breast cancer cell line stimulates β-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the β-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin β1 (HRG)-stimulated cells and both proteins bind to the endogenous β-casein promoter in T47D breast cancer cells. Together, our results establish a novel molecular mechanism of transmembrane receptor signal transduction involving nuclear cotranslocation of the receptor intracellular domain and associated transcription factor. Subsequent binding of the two proteins at transcription factor target promoters results in activation of gene expression. The Rockefeller University Press 2004-11-08 /pmc/articles/PMC2172499/ /pubmed/15534001 http://dx.doi.org/10.1083/jcb.200403155 Text en Copyright © 2004, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Williams, Christopher C.
Allison, June G.
Vidal, Gregory A.
Burow, Matthew E.
Beckman, Barbara S.
Marrero, Luis
Jones, Frank E.
The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone
title The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone
title_full The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone
title_fullStr The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone
title_full_unstemmed The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone
title_short The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone
title_sort erbb4/her4 receptor tyrosine kinase regulates gene expression by functioning as a stat5a nuclear chaperone
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172499/
https://www.ncbi.nlm.nih.gov/pubmed/15534001
http://dx.doi.org/10.1083/jcb.200403155
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