2. Academic Validation
  3. The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling

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.
Atanu Chakraborty 1,  Markus E Diefenbacher 1,  Anastasia Mylona 2,  Olivier Kassel 3,  Axel Behrens 4
Affiliations

Affiliations

  • 1 Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
  • 2 Signal Transduction and Transcription Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
  • 3 Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), Building 304, Room 208A, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen D-76344, Germany.
  • 4 1] Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK [2] School of Medicine, King's College London, Guy's Campus, London SE1 1UL, UK.
PMID: 25851810 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.

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