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Integrins synergise to induce expression of the MRTF-A-SRF target gene ISG15 for promoting cancer cell invasion

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Hermann,  Michaela-Rosemarie
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Jakobson,  Madis
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Colo,  Georgina P.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Rognoni,  Emanuel
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Jakobson,  Maili
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Hermann, M.-R., Jakobson, M., Colo, G. P., Rognoni, E., Jakobson, M., Kupatt, C., et al. (2016). Integrins synergise to induce expression of the MRTF-A-SRF target gene ISG15 for promoting cancer cell invasion. JOURNAL OF CELL SCIENCE, 129(7), 1391-1403. doi:10.1242/jcs.177592.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-E2A9-F
Abstract
Integrin-mediated activation of small GTPases induces the polymerisation of G-actin into various actin structures and the release of the transcriptional co-activator MRTF from G-actin. Here we report that pan-integrin-null fibroblasts seeded on fibronectin and expressing beta 1- and/or alpha V-class integrin contained different G-actin pools, nuclear MRTF-A (also known as MKL1 or MAL) levels and MRTF-A-SRF activities. The nuclear MRTF-A levels and activities were highest in cells expressing both integrin classes, lower in cells expressing beta 1 integrins and lowest in cells expressing the alpha V integrins. Quantitative proteomics and transcriptomics analyses linked the differential MRTF-A activities to the expression of the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which is known to modify focal adhesion and cytoskeletal proteins. The malignant breast cancer cell line MDA-MB-231 expressed high levels of beta 1 integrins, ISG15 and ISGylated proteins, which promoted invasive properties, whereas non-invasive MDA-MB-468 and MCF-7 cell lines expressed low levels of beta 1 integrins, ISG15 and ISGylated proteins. Our findings suggest that integrin-adhesion-induced MRTF-A-SRF activation and ISG15 expression constitute a newly discovered signalling circuit that promotes cell migration and invasion.