Vimentin-ERK signaling uncouples Slug gene regulatory function

Reetta Virtakoivu, Anja Mai, Elina Mattila, Nicola De Franceschi, Susumu Y. Imanishi, Garry Corthals, Riina Kaukonen, Markku Saari, Fang Cheng, Elin Torvaldson, Veli-Matti Kosma, Arto Mannermaa, Ghaffar Muharram, Christine Gilles, John Eriksson, Ylermi Soini, James B. Lorens, Johanna Ivaska

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53 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2349-2362
JournalCancer Research
Volume75
Issue number11
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

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  • Cite this

    Virtakoivu, R., Mai, A., Mattila, E., De Franceschi, N., Imanishi, S. Y., Corthals, G., Kaukonen, R., Saari, M., Cheng, F., Torvaldson, E., Kosma, V-M., Mannermaa, A., Muharram, G., Gilles, C., Eriksson, J., Soini, Y., Lorens, J. B., & Ivaska, J. (2015). Vimentin-ERK signaling uncouples Slug gene regulatory function. Cancer Research, 75(11), 2349-2362. https://doi.org/10.1158/0008-5472.CAN-14-2842