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VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology
Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727759/ https://www.ncbi.nlm.nih.gov/pubmed/31091164 http://dx.doi.org/10.1091/mbc.E19-03-0144 |
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author | Jang, HyeIn Jang, Eun Ryoung Wilson, Patricia G. Anderson, Daniel Galperin, Emilia |
author_facet | Jang, HyeIn Jang, Eun Ryoung Wilson, Patricia G. Anderson, Daniel Galperin, Emilia |
author_sort | Jang, HyeIn |
collection | PubMed |
description | Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the stoichiometry of HUWE1 in the Shoc2 complex as well as HUWE1-mediated allosteric ubiquitination of the Shoc2 scaffold and the RAF-1 kinase. Abrogated ATPase activity leads to augmented ubiquitination of Shoc2/RAF-1 and altered phosphorylation of RAF-1. We found that in fibroblasts from patients with inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) that harbor germline mutations in VCP, the levels of Shoc2 ubiquitination and ERK1/2 phosphorylation are imbalanced. This study provides a mechanistic basis for the critical role of VCP in the regulation of the ERK1/2 pathway and reveals a previously unrecognized function of the ERK1/2 pathway in the pathogenesis of IBMPFD. |
format | Online Article Text |
id | pubmed-6727759 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-67277592019-09-16 VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology Jang, HyeIn Jang, Eun Ryoung Wilson, Patricia G. Anderson, Daniel Galperin, Emilia Mol Biol Cell Brief Reports Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the stoichiometry of HUWE1 in the Shoc2 complex as well as HUWE1-mediated allosteric ubiquitination of the Shoc2 scaffold and the RAF-1 kinase. Abrogated ATPase activity leads to augmented ubiquitination of Shoc2/RAF-1 and altered phosphorylation of RAF-1. We found that in fibroblasts from patients with inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) that harbor germline mutations in VCP, the levels of Shoc2 ubiquitination and ERK1/2 phosphorylation are imbalanced. This study provides a mechanistic basis for the critical role of VCP in the regulation of the ERK1/2 pathway and reveals a previously unrecognized function of the ERK1/2 pathway in the pathogenesis of IBMPFD. The American Society for Cell Biology 2019-07-01 /pmc/articles/PMC6727759/ /pubmed/31091164 http://dx.doi.org/10.1091/mbc.E19-03-0144 Text en © 2019 Jang, Jang, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 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. |
spellingShingle | Brief Reports Jang, HyeIn Jang, Eun Ryoung Wilson, Patricia G. Anderson, Daniel Galperin, Emilia VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology |
title | VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology |
title_full | VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology |
title_fullStr | VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology |
title_full_unstemmed | VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology |
title_short | VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology |
title_sort | vcp/p97 controls signals of the erk1/2 pathway transmitted via the shoc2 scaffolding complex: novel insights into ibmpfd pathology |
topic | Brief Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727759/ https://www.ncbi.nlm.nih.gov/pubmed/31091164 http://dx.doi.org/10.1091/mbc.E19-03-0144 |
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