title: Vimentin-ERK Signaling Uncouples Slug Gene Regulatory Function.
abstract: Epithelial-mesenchymal transition (EMT) in cells is a developmental process adopted during tumorigenesis that promotes metastatic capacity. In this study, we advance understanding of EMT control in cancer cells with the description of a novel vimentin-ERK axis that regulates the transcriptional activity of Slug (SNAI2). Vimentin, ERK, and Slug exhibited overlapping subcellular localization in clinical specimens of triple-negative breast carcinoma. RNAi-mediated ablation of these gene products inhibited cancer cell migration and cell invasion through a laminin-rich matrix. Biochemical analyses demonstrated direct interaction of vimentin and ERK, which promoted ERK activation and enhanced vimentin transcription. Consistent with its role as an intermediate filament, vimentin acted as a scaffold to recruit Slug to ERK and promote Slug phosphorylation at serine-87. Site-directed mutagenesis established a requirement for ERK-mediated Slug phosphorylation in EMT initiation. Together, these findings identified a pivotal step in controlling the ability of Slug to organize hallmarks of EMT.
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors: Reetta
authors: R
authors: Virtakoivu
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors: Anja
authors: A
authors: Mai
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors: Elina
authors: E
authors: Mattila
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors: Nicola
authors: N
authors: De Franceschi
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors: Susumu Y
authors: SY
authors: Imanishi
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors: Garry
authors: G
authors: Corthals
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors: Riina
authors: R
authors: Kaukonen
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors: Markku
authors: M
authors: Saari
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Åbo Akademi University, Turku, Finland.
authors: Fang
authors: F
authors: Cheng
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Åbo Akademi University, Turku, Finland.
authors: Elin
authors: E
authors: Torvaldson
authors: University of Eastern Finland, Cancer Center of Eastern Finland, Kuopio, Finland.
authors: Veli-Matti
authors: VM
authors: Kosma
authors: University of Eastern Finland, Cancer Center of Eastern Finland, Kuopio, Finland.
authors: Arto
authors: A
authors: Mannermaa
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors: Ghaffar
authors: G
authors: Muharram
authors: Université de Liège, GIGA-Cancer, Liege, Belgium.
authors: Christine
authors: C
authors: Gilles
authors: Åbo Akademi University, Turku, Finland.
authors: John
authors: J
authors: Eriksson
authors: University of Eastern Finland, Cancer Center of Eastern Finland, Kuopio, Finland.
authors: Ylermi
authors: Y
authors: Soini
authors: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors: James B
authors: JB
authors: Lorens
authors: Turku Centre for Biotechnology, University of Turku, Turku, Finland. Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland. Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland. johanna.ivaska@utu.fi.
authors: Johanna
authors: J
authors: Ivaska
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002642:Chick Embryo; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D014746:Vimentin / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1