Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin
BMP-SMAD signalling plays a crucial role in numerous biological processes including embryonic development and iron homeostasis. Dysregulation of the iron-regulatory hormone hepcidin is associated with many clinical iron-related disorders. We hypothesised that molecules which mediate BMP-SMAD signall...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566084/ https://www.ncbi.nlm.nih.gov/pubmed/26358513 http://dx.doi.org/10.1038/srep13986 |
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author | Goh, Justin B. Wallace, Daniel F. Hong, Wanjin Nathan Subramaniam, V. |
author_facet | Goh, Justin B. Wallace, Daniel F. Hong, Wanjin Nathan Subramaniam, V. |
author_sort | Goh, Justin B. |
collection | PubMed |
description | BMP-SMAD signalling plays a crucial role in numerous biological processes including embryonic development and iron homeostasis. Dysregulation of the iron-regulatory hormone hepcidin is associated with many clinical iron-related disorders. We hypothesised that molecules which mediate BMP-SMAD signalling play important roles in the regulation of iron homeostasis and variants in these proteins may be potential genetic modifiers of iron-related diseases. We examined the role of endofin, a SMAD anchor, and show that knockdown of endofin in liver cells inhibits basal and BMP-induced hepcidin expression along with other BMP-regulated genes, ID1 and SMAD7. We show for the first time, the in situ interaction of endofin with SMAD proteins and significantly reduced SMAD phosphorylation with endofin knockdown, suggesting that endofin modulates hepcidin through BMP-SMAD signalling. Characterisation of naturally occurring SNPs show that mutations in the conserved FYVE domain result in mislocalisation of endofin, potentially affecting downstream signalling and modulating hepcidin expression. In conclusion, we have identified a hitherto unrecognised link, endofin, between the BMP-SMAD signalling pathway, and the regulation of hepcidin expression and iron homeostasis. This study further defines the molecular network involved in iron regulation and provides potential targets for the treatment of iron-related disorders. |
format | Online Article Text |
id | pubmed-4566084 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45660842015-09-15 Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin Goh, Justin B. Wallace, Daniel F. Hong, Wanjin Nathan Subramaniam, V. Sci Rep Article BMP-SMAD signalling plays a crucial role in numerous biological processes including embryonic development and iron homeostasis. Dysregulation of the iron-regulatory hormone hepcidin is associated with many clinical iron-related disorders. We hypothesised that molecules which mediate BMP-SMAD signalling play important roles in the regulation of iron homeostasis and variants in these proteins may be potential genetic modifiers of iron-related diseases. We examined the role of endofin, a SMAD anchor, and show that knockdown of endofin in liver cells inhibits basal and BMP-induced hepcidin expression along with other BMP-regulated genes, ID1 and SMAD7. We show for the first time, the in situ interaction of endofin with SMAD proteins and significantly reduced SMAD phosphorylation with endofin knockdown, suggesting that endofin modulates hepcidin through BMP-SMAD signalling. Characterisation of naturally occurring SNPs show that mutations in the conserved FYVE domain result in mislocalisation of endofin, potentially affecting downstream signalling and modulating hepcidin expression. In conclusion, we have identified a hitherto unrecognised link, endofin, between the BMP-SMAD signalling pathway, and the regulation of hepcidin expression and iron homeostasis. This study further defines the molecular network involved in iron regulation and provides potential targets for the treatment of iron-related disorders. Nature Publishing Group 2015-09-11 /pmc/articles/PMC4566084/ /pubmed/26358513 http://dx.doi.org/10.1038/srep13986 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Goh, Justin B. Wallace, Daniel F. Hong, Wanjin Nathan Subramaniam, V. Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin |
title | Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin |
title_full | Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin |
title_fullStr | Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin |
title_full_unstemmed | Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin |
title_short | Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin |
title_sort | endofin, a novel bmp-smad regulator of the iron-regulatory hormone, hepcidin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566084/ https://www.ncbi.nlm.nih.gov/pubmed/26358513 http://dx.doi.org/10.1038/srep13986 |
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