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

Research output: Contribution to journalArticleScientificpeer-review

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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 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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Gastropoda
Vimentin
Regulator Genes
Epithelial-Mesenchymal Transition
Phosphorylation
Intermediate Filaments
Laminin
RNA Interference
Site-Directed Mutagenesis
Serine
Cell Movement
Neoplasms
Carcinogenesis
Breast Neoplasms
Genes

Cite this

Virtakoivu, R., Mai, A., Mattila, E., De Franceschi, N., Imanishi, S. Y., Corthals, G., ... 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
Virtakoivu, Reetta ; Mai, Anja ; Mattila, Elina ; De Franceschi, Nicola ; Imanishi, Susumu Y. ; Corthals, Garry ; Kaukonen, Riina ; Saari, Markku ; Cheng, Fang ; Torvaldson, Elin ; Kosma, Veli-Matti ; Mannermaa, Arto ; Muharram, Ghaffar ; Gilles, Christine ; Eriksson, John ; Soini, Ylermi ; Lorens, James B. ; Ivaska, Johanna. / Vimentin-ERK signaling uncouples Slug gene regulatory function. In: Cancer Research. 2015 ; Vol. 75, No. 11. pp. 2349-2362.
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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.",
author = "Reetta Virtakoivu and Anja Mai and Elina Mattila and {De Franceschi}, Nicola and Imanishi, {Susumu Y.} and Garry Corthals and Riina Kaukonen and Markku Saari and Fang Cheng and Elin Torvaldson and Veli-Matti Kosma and Arto Mannermaa and Ghaffar Muharram and Christine Gilles and John Eriksson and Ylermi Soini and Lorens, {James B.} and Johanna Ivaska",
year = "2015",
doi = "10.1158/0008-5472.CAN-14-2842",
language = "English",
volume = "75",
pages = "2349--2362",
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Virtakoivu, R, Mai, A, Mattila, E, De Franceschi, N, Imanishi, SY, Corthals, G, Kaukonen, R, Saari, M, Cheng, F, Torvaldson, E, Kosma, V-M, Mannermaa, A, Muharram, G, Gilles, C, Eriksson, J, Soini, Y, Lorens, JB & Ivaska, J 2015, 'Vimentin-ERK signaling uncouples Slug gene regulatory function', Cancer Research, vol. 75, no. 11, pp. 2349-2362. https://doi.org/10.1158/0008-5472.CAN-14-2842

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

In: Cancer Research, Vol. 75, No. 11, 2015, p. 2349-2362.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Vimentin-ERK signaling uncouples Slug gene regulatory function

AU - Virtakoivu, Reetta

AU - Mai, Anja

AU - Mattila, Elina

AU - De Franceschi, Nicola

AU - Imanishi, Susumu Y.

AU - Corthals, Garry

AU - Kaukonen, Riina

AU - Saari, Markku

AU - Cheng, Fang

AU - Torvaldson, Elin

AU - Kosma, Veli-Matti

AU - Mannermaa, Arto

AU - Muharram, Ghaffar

AU - Gilles, Christine

AU - Eriksson, John

AU - Soini, Ylermi

AU - Lorens, James B.

AU - Ivaska, Johanna

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-14-2842

DO - 10.1158/0008-5472.CAN-14-2842

M3 - Article

VL - 75

SP - 2349

EP - 2362

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 11

ER -

Virtakoivu R, Mai A, Mattila E, De Franceschi N, Imanishi SY, Corthals G et al. Vimentin-ERK signaling uncouples Slug gene regulatory function. Cancer Research. 2015;75(11):2349-2362. https://doi.org/10.1158/0008-5472.CAN-14-2842