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High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells

Endoglin (ENG) is a single-pass transmembrane protein highly expressed on vascular endothelial cells, although low expression levels can be detected in many other cell types. Its extracellular domain can be found in circulation known as soluble endoglin (sENG). Levels of sENG are elevated in many pa...

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Autores principales: Andersson-Rusch, Clara, Liu, Bin, Quist-Løkken, Ingrid, Upton, Paul D., Olsen, Oddrun Elise, Hella, Hanne, Yang, Xudong, Tong, Zhen, Morrell, Nicholas W., Holien, Toril, Li, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10126157/
https://www.ncbi.nlm.nih.gov/pubmed/37095146
http://dx.doi.org/10.1038/s41598-023-33352-3
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author Andersson-Rusch, Clara
Liu, Bin
Quist-Løkken, Ingrid
Upton, Paul D.
Olsen, Oddrun Elise
Hella, Hanne
Yang, Xudong
Tong, Zhen
Morrell, Nicholas W.
Holien, Toril
Li, Wei
author_facet Andersson-Rusch, Clara
Liu, Bin
Quist-Løkken, Ingrid
Upton, Paul D.
Olsen, Oddrun Elise
Hella, Hanne
Yang, Xudong
Tong, Zhen
Morrell, Nicholas W.
Holien, Toril
Li, Wei
author_sort Andersson-Rusch, Clara
collection PubMed
description Endoglin (ENG) is a single-pass transmembrane protein highly expressed on vascular endothelial cells, although low expression levels can be detected in many other cell types. Its extracellular domain can be found in circulation known as soluble endoglin (sENG). Levels of sENG are elevated in many pathological conditions, in particular preeclampsia. We have shown that while loss of cell surface ENG decreases BMP9 signaling in endothelial cells, knocking down ENG in blood cancer cells enhances BMP9 signaling. Despite sENG binding to BMP9 with high affinity and blocking the type II receptor binding site on BMP9, sENG did not inhibit BMP9 signaling in vascular endothelial cells, but the dimeric form of sENG inhibited BMP9 signaling in blood cancer cells. Here we report that in non-endothelial cells such as human multiple myeloma cell lines and the mouse myoblast cell line C2C12, both monomeric and dimeric forms of sENG inhibit BMP9 signaling when present at high concentrations. Such inhibition can be alleviated by the overexpression of ENG and ACVRL1 (encoding ALK1) in the non-endothelial cells. Our findings suggest that the effects of sENG on BMP9 signaling is cell-type specific. This is an important consideration when developing therapies targeting the ENG and ALK1 pathway.
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spelling pubmed-101261572023-04-26 High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells Andersson-Rusch, Clara Liu, Bin Quist-Løkken, Ingrid Upton, Paul D. Olsen, Oddrun Elise Hella, Hanne Yang, Xudong Tong, Zhen Morrell, Nicholas W. Holien, Toril Li, Wei Sci Rep Article Endoglin (ENG) is a single-pass transmembrane protein highly expressed on vascular endothelial cells, although low expression levels can be detected in many other cell types. Its extracellular domain can be found in circulation known as soluble endoglin (sENG). Levels of sENG are elevated in many pathological conditions, in particular preeclampsia. We have shown that while loss of cell surface ENG decreases BMP9 signaling in endothelial cells, knocking down ENG in blood cancer cells enhances BMP9 signaling. Despite sENG binding to BMP9 with high affinity and blocking the type II receptor binding site on BMP9, sENG did not inhibit BMP9 signaling in vascular endothelial cells, but the dimeric form of sENG inhibited BMP9 signaling in blood cancer cells. Here we report that in non-endothelial cells such as human multiple myeloma cell lines and the mouse myoblast cell line C2C12, both monomeric and dimeric forms of sENG inhibit BMP9 signaling when present at high concentrations. Such inhibition can be alleviated by the overexpression of ENG and ACVRL1 (encoding ALK1) in the non-endothelial cells. Our findings suggest that the effects of sENG on BMP9 signaling is cell-type specific. This is an important consideration when developing therapies targeting the ENG and ALK1 pathway. Nature Publishing Group UK 2023-04-24 /pmc/articles/PMC10126157/ /pubmed/37095146 http://dx.doi.org/10.1038/s41598-023-33352-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Andersson-Rusch, Clara
Liu, Bin
Quist-Løkken, Ingrid
Upton, Paul D.
Olsen, Oddrun Elise
Hella, Hanne
Yang, Xudong
Tong, Zhen
Morrell, Nicholas W.
Holien, Toril
Li, Wei
High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells
title High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells
title_full High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells
title_fullStr High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells
title_full_unstemmed High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells
title_short High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells
title_sort high concentrations of soluble endoglin can inhibit bmp9 signaling in non-endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10126157/
https://www.ncbi.nlm.nih.gov/pubmed/37095146
http://dx.doi.org/10.1038/s41598-023-33352-3
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