title: Regulation of the localisation and function of the oncogene LYRIC/AEG-1 by ubiquitination at K486 and K491.
abstract: The pivotal role of LYRIC/AEG-1 in malignant transformation, tumourigenesis and chemo-resistance has previously been demonstrated in different cell types and sub-cellular compartments. The localisation of LYRIC/AEG-1 appears crucial to its function and is regulated by three lysine-rich nuclear localisation signal regions, one of which was previously demonstrated to be modified by ubiquitin. Here we show that mutation of LYRIC/AEG-1 at K486 and K491 results in a loss of ubiquitination. A K486/491R double mutant that is incapable of ubiquitination shows reduced binding to the NFκB subunit p65 or importin-β resulting in a distinctive peri-nuclear localisation of LYRIC/AEG-1. We also provide evidence to suggest that TOPORS, an E3 ligase that also regulates p53 modification may be responsible for LYRIC/AEG-1 ubiquitin modification. Overall we demonstrate that specific sites of LYRIC/AEG-1 ubiquitination are essential for regulating LYRIC/AEG-1 localisation and functionally interacting proteins.
authors: Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors: Hayley J
authors: HJ
authors: Luxton
authors: Protein Analysis and Proteomics, Cancer Research UK London Research Institute, London WC2A 3LY, UK; Protein Analysis and Proteomics, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Potters Bar EN6 3LD, UK.
authors: Karin
authors: K
authors: Barnouin
authors: Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors: Gavin
authors: G
authors: Kelly
authors: Protein Analysis and Proteomics, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors: Sarah
authors: S
authors: Hanrahan
authors: Protein Analysis and Proteomics, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors: Nick
authors: N
authors: Totty
authors: Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors: David E
authors: DE
authors: Neal
authors: Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Electronic address: Hayley.Whitaker@cruk.cam.ac.uk.
authors: Hayley C
authors: HC
authors: Whitaker
mesh_terms: D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D008565:Membrane Proteins; D017354:Point Mutation; D060066:Protein Interaction Maps; D016601:RNA-Binding Proteins; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D025801:Ubiquitin
keywords: Localisation; Oncogene; Protein–protein interaction; Ubiquitin