The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling
journal contributionposted on 09.07.2020, 13:58 by Atanu Chakraborty, Markus E Diefenbacher, Anastasia Mylona, Olivier Kassel, Axel Behrens
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.
AnimalsApoptosisCarrier ProteinsCell Line, TumorCell ProliferationHEK293 CellsHeLa CellsHumansLung NeoplasmsMAP Kinase Signaling SystemMiceMice, TransgenicNeoplasm TransplantationPhosphorylationProto-Oncogene Proteins c-junProto-Oncogene Proteins c-mycRibosomal Protein S6 Kinases, 90-kDaSignal TransductionTrans-ActivatorsTranscription Factor AP-1Ubiquitin-Protein LigasesUbiquitinationraf Kinasesras ProteinsHela CellsBehrensBRF-ackHP-ackPC-ackHTS-ackPRT-ack