Integrins synergize 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 β1- and/or αV-class integrin expressing pan-integrin-null fibroblasts seeded on fibronectin (FN) contained different G-actin pools, nuclear MRTF-A 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-class integrins and lowest in cells expressing the αV-class 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 FA 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, while 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 new signalling circuit that promotes cell migration and invasion.