The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling

Nat Commun. 2015 Apr 8;6:6782. doi: 10.1038/ncomms7782.

Abstract

The c-Jun/AP-1 transcription factor controls key cellular behaviours, including proliferation and apoptosis, in response to JNK and Ras/MAPK signalling. While the JNK pathway has been well characterized, the mechanism of activation by Ras was elusive. Here we identify the uncharacterized ubiquitin ligase Trim7 as a critical component of AP-1 activation via Ras. We found that MSK1 directly phosphorylates Trim7 in response to direct activation by the Ras-Raf-MEK-ERK pathway, and this modification stimulates Trim7 E3 ubiquitin ligase activity. Trim7 mediates Lys63-linked ubiquitination of the AP-1 co-activator RACO-1, leading to RACO-1 protein stabilization. Consequently, Trim7 depletion reduces RACO-1 levels and AP-1-dependent gene expression. Moreover, transgenic overexpression of Trim7 increases lung tumour burden in a Ras-driven cancer model, and knockdown of Trim7 in established xenografts reduces tumour growth. Thus, phosphorylation-ubiquitination crosstalk between MSK1, Trim7 and RACO-1 completes the long sought-after mechanism linking growth factor signalling and AP-1 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lung Neoplasms / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • raf Kinases / metabolism*
  • ras Proteins / metabolism*

Substances

  • Carrier Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-myc
  • Trans-Activators
  • Transcription Factor AP-1
  • RNF187 protein, human
  • TRIM7 protein, human
  • Ubiquitin-Protein Ligases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • raf Kinases
  • ras Proteins