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

Mol Biol Cell. 2019 Jul 1;30(14):1655-1663. doi: 10.1091/mbc.E19-03-0144. Epub 2019 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endosomes / metabolism
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / pathology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System*
  • Models, Biological
  • Muscular Dystrophies, Limb-Girdle / metabolism*
  • Muscular Dystrophies, Limb-Girdle / pathology*
  • Myositis, Inclusion Body / metabolism*
  • Myositis, Inclusion Body / pathology*
  • Osteitis Deformans / metabolism*
  • Osteitis Deformans / pathology*
  • Ubiquitination
  • Valosin Containing Protein / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • SHOC2 protein, human
  • Valosin Containing Protein

Supplementary concepts

  • Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia