title: PDLIM2 regulates transcription factor activity in epithelial-to-mesenchymal transition via the COP9 signalosome.
abstract: Epithelial cell differentiation and polarized migration associated with epithelial-to-mesenchymal transition (EMT) in cancer requires integration of gene expression with cytoskeletal dynamics. Here we show that the PDZ-LIM domain protein PDLIM2 (Mystique/SLIM), a known cytoskeletal protein and promoter of nuclear nuclear factor κB (NFκB) and signal transducer and activator of transcription (STAT) degradation, regulates transcription factor activity and gene expression through the COP9 signalosome (CSN). Although repressed in certain cancers, PDLIM2 is highly expressed in invasive cancer cells. Here we show that PDLIM2 suppression causes loss of directional migration, inability to polarize the cytoskeleton, and reversal of the EMT phenotype. This is accompanied by altered activity of several transcription factor families, including β-catenin, Ap-1, NFκB, interferon regulatory factors, STATs, JUN, and p53. We also show that PDLIM2 associates with CSN5, and cells with suppressed PDLIM2 exhibit reduced nuclear accumulation and deneddylation activity of the CSN toward the cullin 1 and cullin 3 subunits of cullin-RING ubiquitin ligases. Thus PDLIM2 integrates cytoskeleton signaling with gene expression in epithelial differentiation by controlling the stability of key transcription factors and CSN activity.
authors.affiliation: Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland Pfizer-Universidad de Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada 18016, Spain.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Bowe
authors.forename: Orla T
authors.initials: OT
authors.lastname: Cox
authors.forename: Verónica
authors.initials: V
authors.lastname: Ayllón
authors.forename: Emilie
authors.initials: E
authors.lastname: Tresse
authors.forename: Nollaig C
authors.initials: NC
authors.lastname: Healy
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Edmunds
authors.forename: Merei
authors.initials: M
authors.lastname: Huigsloot
authors.forename: Rosemary
authors.initials: R
authors.lastname: O'Connor
mesh_terms: D000075686:COP9 Signalosome Complex; D002454:Cell Differentiation; D002465:Cell Movement; D016764:Cell Polarity; D004847:Epithelial Cells / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000502:physiology*; D061986:MCF-7 Cells; D008840:Microfilament Proteins / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D021381:Protein Transport; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; C502929:PDLIM2 protein, human; D051176:beta Catenin; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex