title: Integrins synergise to induce expression of the MRTF-A-SRF target gene ISG15 for promoting cancer cell invasion.
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 β1- and/or αV-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 β1 integrins and lowest in cells expressing the αV 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 β1 integrins, ISG15 and ISGylated proteins, which promoted invasive properties, whereas non-invasive MDA-MB-468 and MCF-7 cell lines expressed low levels of β1 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.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Michaela-Rosemarie
authors.initials: MR
authors.lastname: Hermann
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Madis
authors.initials: M
authors.lastname: Jakobson
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Georgina P
authors.initials: GP
authors.lastname: Colo
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Rognoni
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Maili
authors.initials: M
authors.lastname: Jakobson
authors.affiliation: Medical Department, Cardiology, Klinikum rechts der Isar-Technische Universität München, Munich 81675, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.affiliation: Institute of Physiological Chemistry, Halle 06114, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Posern
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany faessler@biochem.mpg.de.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D016207:Cytokines; D039564:Integrin alphaV; D019012:Integrin beta1; C431575:MRTFA protein, human; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014452:Ubiquitins; C074034:ISG15 protein, human
keywords: Cell migration; ISG15; Integrin; MRTF-A; SRF