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.

Micropatterning as a tool to identify regulatory triggers and kinetics of actin-mediated endothelial mechanosensing

“…In good agreement with our finding that an increase in the adhesive area results in the nuclear accumulation of MRTF-A, recent work by Plessner and colleagues established a connection between integrin signaling, Rho GTPase activation and SRF-mediated transcription via nuclear actin polymerization (Plessner et al, 2015). This is consistent with results from Hermann et al, who demonstrated that integrin signaling synergizes to trigger the expression of the invasion-promoting SRF target gene ISG15 (Hermann et al, 2016).…”

Establishment and Characterization of a New Triple Negative Breast Cancer Cell Line from an Iranian Breast Cancer Tissue

“…CD29, also known as Integrin β1, is a protein involved in cell motility and cancer metastasis. The malignant breast cancer cell line, MDA-MB-231, expresses high levels of β1 integrins, which promote invasive properties, whereas non-invasive MCF-7 cell line expresses low levels of β1 integrins (Hermann et al, 2016). It has been shown that the lack of CD29 results in a decreased cell migration (Vassilopoulos et al, 2014).…”

Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

“…Given that DOCK6 depletion was associated with cytoskeleton alterations and increased G-actin levels, one possibility was that cytoplasmic G-actin sequestered the myocardin-related transcription factor A/serum response factor (MRTF-A/SRF) transcription complex in the cytoplasm, blocking nuclear translocation and subsequent ISG15 gene transcription (Hermann et al, 2016). Consistent with this hypothesis, MRTF-A distribution was more cytoplasmic and synthetic promoterreporter assays revealed lower MRTF-A/SRF transcriptional activity in DOCK6 KO cells compared to control cells.…”