MAL/MRTF-A controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins

Abstract

SummaryMonomeric actin regulates gene expression through serum response factor (SRF) by inhibiting its transcriptional coactivator myocardinrelated transcription factor (MAL/MRTF). Many affected genes encode cytoskeletal components. We have analysed the migratory effects of actin-MAL signalling and of new target genes in non-invasive highly adherent cells. Expression of active MAL impaired migration of both fibroblasts and epithelial cells, whereas dominant-negative constructs and partial knockdown of MAL/MRTF enhanced motility. Knockdown of three newly characterised G-actin-regulated MAL targets, integrin a5, plakophilin 2 (Pkp2) and FHL1, enhanced cell migration. All three were upregulated by external stimulation through actin-MAL-SRF signalling, and MAL and SRF were inducibly recruited to cis-regulatory elements of the integrin a5 and Pkp2 genes. Finally, the reduced migration of epithelial cells stably expressing MAL was partially reversed by knockdown of Pkp2 and FHL1. We conclude that the actin-MAL pathway promotes adhesive gene expression, including integrin a5, Pkp2 and FHL1, and that this is anti-motile for non-invasive cells harbouring high basal activity.

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

“…Furthermore, loss of CDH11 either in Cdh11 −/− mouse dermal fibroblasts or in shCDH11 human dermal fibroblasts abolished the expression of transcription factors known to affect ECM synthesis (Ueyama et al, 2003;Medjkane et al, 2009;Small et al, 2010;Leitner et al, 2011;Velasquez et al, 2013;Johnson et al, 2014;Parreno et al, 2014), such as MYOCD, MRTF-A, SRF and to a lesser extent MRTF-B. In agreement, knocking down either MYOCD or MRTF-A and -B decreased CDH11-mediated expression of collagen and elastin, but the effects of MRTF-A and -B were significantly stronger.…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…In contrast, loss of MRTF-A reduced the levels of DSG1 messenger RNA (mRNA) in keratinocytes, suggesting that DSG1 is directly regulated by the SRF/MRTF-A complex . Another experiment showed that MRTF-A and SRF were recruited to cis-regulatory elements of the PKP2 gene to regulate its expression (Leitner et al 2011). Taken together, these data suggest that RhoA/MRTF-A signaling in keratinocytes affects the expression of desmosomal proteins directly and indirectly although the regulation via SRF/MRTF-A in response to mechanical strain has not been directly shown.…”

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

“…1a-d) that MRFT-A induced hallmarks of angiogenesisthat is, migration and tube formation of cultured human microvascular endothelial cells-to a similar extent as T 4. The pro-angiogenic effect of MRTF-A was dependent on the G-acting-binding motif of T 4, as mutating this domain and annihilating G-acting binding abolished the T 4 effect on vessel growth, as did a short-hairpin RNA (shRNA) interfering simultaneously with MRTF-A and B transcription (MRTF-shRNA) 27 . Consistently, T 4 enhanced nuclear MRTF-A translocation (Fig.…”