VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: Novel insights into IBMPFD pathology

Hye In Jang; Eun Ryoung Jang; Patricia G. Wilson; Daniel Anderson; Emilia Galperin

doi:10.1091/mbc.E19-03-0144

VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: Novel insights into IBMPFD pathology

Hye In Jang, Eun Ryoung Jang, Patricia G. Wilson, Daniel Anderson, Emilia Galperin

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1655-1663
Number of pages	9
Journal	Molecular Biology of the Cell
Volume	30
Issue number	14
DOIs	https://doi.org/10.1091/mbc.E19-03-0144
State	Published - Jul 1 2019

Bibliographical note

Funding Information:
We thank Tianyan Gao, Louis Hersh, Charles Waechter, and Craig Vander Kooi for providing reagents and critical reading of the manuscript. The UK Flow Cytometry and Cell Sorting core facility is supported in part by the UK Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (Grant no. P30 CA177558). This project was supported by grants from the National Cancer Institute (Grant no. R00CA126161 to E.G.), the National Institute of General Medical Sciences (Grant no. GM113087 to E.G.), the American Cancer Society (Grant no. RSG-14-172-01-CSM to E.G.), and the American Heart Association (Grant no. 15PRE25090207 to H.I.J.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2019 Jang, Jang, et al.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1091/mbc.E19-03-0144

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title = "VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: Novel insights into IBMPFD pathology",

abstract = "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.",

author = "Jang, {Hye In} and Jang, {Eun Ryoung} and Wilson, {Patricia G.} and Daniel Anderson and Emilia Galperin",

note = "Funding Information: We thank Tianyan Gao, Louis Hersh, Charles Waechter, and Craig Vander Kooi for providing reagents and critical reading of the manuscript. The UK Flow Cytometry and Cell Sorting core facility is supported in part by the UK Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (Grant no. P30 CA177558). This project was supported by grants from the National Cancer Institute (Grant no. R00CA126161 to E.G.), the National Institute of General Medical Sciences (Grant no. GM113087 to E.G.), the American Cancer Society (Grant no. RSG-14-172-01-CSM to E.G.), and the American Heart Association (Grant no. 15PRE25090207 to H.I.J.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2019 Jang, Jang, et al.",

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AU - Wilson, Patricia G.

AU - Anderson, Daniel

AU - Galperin, Emilia

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N2 - 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.

AB - 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.

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ER -

VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: Novel insights into IBMPFD pathology

Abstract

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