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

Author

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  • Atanu Chakraborty

    (Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories)

  • Markus E. Diefenbacher

    (Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories)

  • Anastasia Mylona

    (Signal Transduction and Transcription Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories)

  • Olivier Kassel

    (Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG))

  • Axel Behrens

    (Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories
    School of Medicine, King's College London)

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.

Suggested Citation

  • Atanu Chakraborty & Markus E. Diefenbacher & Anastasia Mylona & Olivier Kassel & Axel Behrens, 2015. "The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7782
    DOI: 10.1038/ncomms7782
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    Cited by:

    1. Maria Gonzalez-Orozco & Hsiang-chi Tseng & Adam Hage & Hongjie Xia & Padmanava Behera & Kazi Afreen & Yoatzin Peñaflor-Tellez & Maria I. Giraldo & Matthew Huante & Lucinda Puebla-Clark & Sarah Tol & A, 2024. "TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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