TY - JOUR
T1 - VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex
T2 - Novel insights into IBMPFD pathology
AU - Jang, Hye In
AU - Jang, Eun Ryoung
AU - Wilson, Patricia G.
AU - Anderson, Daniel
AU - Galperin, Emilia
N1 - Publisher Copyright:
© 2019 Jang, Jang, et al.
PY - 2019/7/1
Y1 - 2019/7/1
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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U2 - 10.1091/mbc.E19-03-0144
DO - 10.1091/mbc.E19-03-0144
M3 - Article
C2 - 31091164
AN - SCOPUS:85069235893
SN - 1059-1524
VL - 30
SP - 1655
EP - 1663
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 14
ER -