Vimentin-ERK Signaling Uncouples Slug Gene Regulatory Function.

Animals; Carcinogenesis/genetics; Cell Movement/genetics; Cell Proliferation/genetics; Chick Embryo; Epithelial-Mesenchymal Transition/genetics; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinase 1/biosynthesis/genetics; Neoplasm Invasiveness/genetics; Neoplasm Metastasis; Phosphorylation; Transcription Factors/biosynthesis/genetics; Triple Negative Breast Neoplasms/genetics/pathology; Vimentin/biosynthesis/genetics; Xenograft Model Antitumor Assays

Abstract :

[en] 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.

Disciplines :

Oncology

Author, co-author :

Virtakoivu, Reetta

Mai, Anja

Mattila, Elina

De Franceschi, Nicola

Imanishi, Susumu Y.

Corthals, Garry

Kaukonen, Riina

Saari, Markku

Cheng, Fang

Torvaldson, Elin

More authors (8 more)

Language :

English

Title :

Vimentin-ERK Signaling Uncouples Slug Gene Regulatory Function.

Publication date :

2015

Journal title :

Cancer Research

ISSN :

0008-5472

eISSN :

1538-7445

Publisher :

American Association for Cancer Research, United States - Maryland

Volume :

Issue :

Pages :

2349-62

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 09 February 2016

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Bibliography

Moustakas A, Heldin CH. Induction of epithelial-mesenchymal transition by transforming growth factor beta. Semin Cancer Biol 2012; 22: 446-54.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871-90.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-74.
De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013; 13: 97-110.
Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol 2014; 16: 488-94.
Perou CM Molecular stratification of triple-negative breast cancers. Oncologist 2010; 15(SUPPL. 5): 39-48.
Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012; 486: 395-9.
Satelli A, Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 2011; 68: 3033-46.
Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012; 148: 1015-28.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704-15.
Gilles C, Polette M, Zahm JM, Tournier JM, Volders L, Foidart JM, et al. Vimentin contributes to human mammary epithelial cell migration. J Cell Sci 1999; 112: 4615-25.
Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 2010; 24: 1838-51.
Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, et al. Vimentin regulates EMT induction by slug and oncogenic H-ras and migration by governing axl expression in breast cancer. Oncogene 2011; 30: 1436-48.
Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 2013; 15: 677-87.
Shin S, Dimitri CA, Yoon SO, Dowdle W, Blenis J. ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol Cell 2010; 38: 114-27.
Radtke S, Milanovic M, Rosse C, DeRycker M, Lachmann S, Hibbert A, et al. ERK2 but not ERK1 mediates HGF-induced motility in non-small cell lung carcinoma cell lines. J Cell Sci 2013; 126: 2381-91.
von Thun A, Birtwistle M, Kalna G, Grindlay J, Strachan D, Kolch W, et al. ERK2 drives tumour cell migration in three-dimensional microenvironments by suppressing expression of Rab17 and liprin-beta2. J Cell Sci 2012; 125: 1465-77.
Botta GP, Reginato MJ, Reichert M, Rustgi AK, Lelkes PI. Constitutive K-RasG12D activation of ERK2 specifically regulates 3D invasion of human pancreatic cancer cells via MMP-1. Mol Cancer Res 2012; 10: 183-96.
Ivaska J, Pallari HM, Nevo J, Eriksson JE. Novel functions of vimentin in cell adhesion, migration, and signaling. Exp Cell Res 2007; 313: 2050-62.
Perlson E, Michaelevski I, Kowalsman N, Ben-Yaakov K, Shaked M, Seger R, et al. Vimentin binding to phosphorylated ERK sterically hinders enzymatic dephosphorylation of the kinase. J Mol Biol 2006; 364: 938-44.
Nieto MA, Cano A. The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin Cancer Biol 2012; 22: 361-8.
Zhang K, Rodriguez-Aznar E, Yabuta N, Owen RJ, Mingot JM, Nojima H, et al. Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation. EMBO J 2012; 31: 29-43.
Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931-40.
Molina-Ortiz P, Villarejo A, MacPherson M, Santos V, Montes A, Souchelnytskyi S, et al. Characterization of the SNAG and SLUG domains of Snail2 in the repression of E-cadherin and EMT induction: modulation by serine 4 phosphorylation. PLoS One 2012; 7: e36132.
Wu ZQ, Li XY, Hu CY, Ford M, Kleer CG, Weiss SJ. Canonical wnt signaling regulates slug activity and links epithelial-mesenchymal transition with epigenetic breast cancer 1, early onset (BRCA1) repression. Proc Natl Acad Sci U S A 2012; 109: 16654-9.
Kao SH, Wang WL, Chen CY, Chang YL, Wu YY, Wang YT, et al. GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug. Oncogene 2014; 33: 3172-82.
Kim JY, Kim YM, Yang CH, Cho SK, Lee JW, Cho M. Functional regulation of slug/Snail2 is dependent on GSK-3beta-mediated phosphorylation. FEBS J 2012; 279: 2929-39.
Chen H, Zhu G, Li Y, Padia RN, Dong Z, Pan ZK, et al. Extracellular signalregulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res 2009; 69: 9228-35.
Geradts J, de Herreros AG, Su Z, Burchette J, Broadwater G, Bachelder RE. Nuclear Snail1 and nuclear ZEB1 protein expression in invasive and intraductal human breast carcinomas. Hum Pathol 2011; 42: 1125-31.
Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y. Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with anaggressive tumour phenotype. Breast Cancer Res Treat 2013; 138: 81-90.
Bartholomeusz C, Gonzalez-Angulo AM, Liu P, Hayashi N, Lluch A, Ferrer-Lozano J, et al. High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients. Oncologist 2012; 17: 766-74.
Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk betweenMAPK signaling pathways inthe regulation of cell survival. FASEB J 2008; 22: 954-65.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3: 11-22.
Matallanas D, Crespo P. New druggable targets in the ras pathway? Curr Opin Mol Ther 2010; 12: 674-83.
Slorach EM, Chou J, Werb Z. Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. Genes Dev 2011; 25: 471-84.
Dominguez D, Montserrat-Sentis B, Virgos-Soler A, Guaita S, Grueso J, Porta M, et al. Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor. Mol Cell Biol 2003; 23: 5078-89.
MacPherson MR, Molina P, Souchelnytskyi S, Wernstedt C, Martin-Perez J, Portillo F, et al. Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail 1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A. Mol Biol Cell 2010; 21: 244-53.
Ivaska J, Vuoriluoto K, Huovinen T, Izawa I, Inagaki M, Parker PJ. PKCepsilon-mediated phosphorylation of vimentin controls integrin recycling and motility. EMBO J 2005; 24: 3834-45.
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2013; 19: 279-90.