Vimentin-ERK Signaling Uncouples Slug Gene Regulatory Function

R Virtakoivu, A Mai, E Mattila, De Franceschi N, SY Imanishi, G Corthals, R Kaukonen, M Saari, Fang Cheng, Elin Torvaldson, VM Kosma, A Mannermaa, G Muharram, C Gilles, John Eriksson, Y Soini, JB Lorens, J Ivaska

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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 Slugphosphorylation in EMT initiation. Together, these findings identified a pivotal step in controlling the ability of Slug to organize hallmarks of EMT.
Original languageUndefined/Unknown
Pages (from-to)2349–2362
Number of pages14
JournalCancer Research
Volume75
Issue number11
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

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