title: The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling.
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.
authors: Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors: Atanu
authors: A
authors: Chakraborty
authors: Mammalian Genetics Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors: Markus E
authors: ME
authors: Diefenbacher
authors: Signal Transduction and Transcription Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors: Anastasia
authors: A
authors: Mylona
authors: 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.
authors: Olivier
authors: O
authors: Kassel
authors: 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.
authors: Axel
authors: A
authors: Behrens
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C489427:MYC protein, human; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D000070584:Tripartite Motif Proteins; C582733:RNF187 protein, human; C458504:TRIM7 protein, human; D044767:Ubiquitin-Protein Ligases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048490:raf Kinases; D018631:ras Proteins