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

Research output: Contribution to journalArticlepeer-review

8 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 languageEnglish
Pages (from-to)1655-1663
Number of pages9
JournalMolecular Biology of the Cell
Volume30
Issue number14
DOIs
StatePublished - Jul 1 2019

Bibliographical note

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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