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

    Chakraborty, A. and Diefenbacher, M.E. and Mylona, Anastasia and Kassel, O. and Behrens, A. (2015) The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling. Nature Communications 6 (1), ISSN 2041-1723.

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    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.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 13 Nov 2018 15:01
    Last Modified: 13 Nov 2018 15:01
    URI: http://eprints.bbk.ac.uk/id/eprint/25125

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