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Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension

A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. He...

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Autores principales: Marsboom, Glenn, Chen, Zhenlong, Yuan, Yang, Zhang, Yanmin, Tiruppathi, Chinnaswamy, Loyd, James E., Austin, Eric D., Machado, Roberto F., Minshall, Richard D., Rehman, Jalees, Malik, Asrar B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415014/
https://www.ncbi.nlm.nih.gov/pubmed/28468941
http://dx.doi.org/10.1091/mbc.E16-11-0790
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author Marsboom, Glenn
Chen, Zhenlong
Yuan, Yang
Zhang, Yanmin
Tiruppathi, Chinnaswamy
Loyd, James E.
Austin, Eric D.
Machado, Roberto F.
Minshall, Richard D.
Rehman, Jalees
Malik, Asrar B.
author_facet Marsboom, Glenn
Chen, Zhenlong
Yuan, Yang
Zhang, Yanmin
Tiruppathi, Chinnaswamy
Loyd, James E.
Austin, Eric D.
Machado, Roberto F.
Minshall, Richard D.
Rehman, Jalees
Malik, Asrar B.
author_sort Marsboom, Glenn
collection PubMed
description A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1–null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation.
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spelling pubmed-54150142017-07-16 Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension Marsboom, Glenn Chen, Zhenlong Yuan, Yang Zhang, Yanmin Tiruppathi, Chinnaswamy Loyd, James E. Austin, Eric D. Machado, Roberto F. Minshall, Richard D. Rehman, Jalees Malik, Asrar B. Mol Biol Cell Articles A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1–null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation. The American Society for Cell Biology 2017-05-01 /pmc/articles/PMC5415014/ /pubmed/28468941 http://dx.doi.org/10.1091/mbc.E16-11-0790 Text en © 2017 Marsboom et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Marsboom, Glenn
Chen, Zhenlong
Yuan, Yang
Zhang, Yanmin
Tiruppathi, Chinnaswamy
Loyd, James E.
Austin, Eric D.
Machado, Roberto F.
Minshall, Richard D.
Rehman, Jalees
Malik, Asrar B.
Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
title Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
title_full Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
title_fullStr Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
title_full_unstemmed Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
title_short Aberrant caveolin-1–mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
title_sort aberrant caveolin-1–mediated smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474dela) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415014/
https://www.ncbi.nlm.nih.gov/pubmed/28468941
http://dx.doi.org/10.1091/mbc.E16-11-0790
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