Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

Abstract

Both the MRTF-SRF and the YAP-TEAD transcriptional regulatory networks respond to extracellular signals and mechanical stimuli. We show that the MRTF-SRF pathway is activated in cancer-associated fibroblasts (CAFs). The MRTFs are required in addition to the YAP pathway for CAF contractile and proinvasive properties. We compared MRTF-SRF and YAP-TEAD target gene sets and identified genes directly regulated by one pathway, the other, or both. Nevertheless, the two pathways exhibit mutual dependence. In CAFs, expression of direct MRTF-SRF genomic targets is also dependent on YAP-TEAD activity, and, conversely, YAP-TEAD target gene expression is also dependent on MRTF-SRF signaling. In normal fibroblasts, expression of activated MRTF derivatives activates YAP, while activated YAP derivatives activate MRTF. Cross-talk between the pathways requires recruitment of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD) and is therefore indirect, arising as a consequence of activation of their target genes. In both CAFs and normal fibroblasts, we found that YAP-TEAD activity is sensitive to MRTF-SRF-induced contractility, while MRTF-SRF signaling responds to YAP-TEAD-dependent TGFβ signaling. Thus, the MRF-SRF and YAP-TEAD pathways interact indirectly through their ability to control cytoskeletal dynamics.

RASSF 1A is required for the maintenance of nuclear actin levels

“…Intriguingly, nuclear actin levels have also been described to contribute to the regulation of Hippo pathway (e.g. SRF regulation of YAP; Sen et al, 2015;Foster et al, 2017), apoptosis (Sharili et al, 2016), differentiation (Xu et al, 2010;Sen et al, 2015Sen et al, , 2017 and DNA damage/ repair (Yuan & Shen, 2001;Belin et al, 2015). Altogether, our findings indicate that loss of RASSF1A expression results in failure to export nuclear actin, suggesting that both regulatory processes are linked and that the clinical data associated with RASSF1 methylation involve deregulated MRTF-A/SRF.…”

“…SRF regulation of YAP; Sen et al, 2015;Foster et al, 2017), apoptosis (Sharili et al, 2016), differentiation (Xu et al, 2010;Sen et al, 2015Sen et al, , 2017 and DNA damage/ repair (Yuan & Shen, 2001;Belin et al, 2015). Intriguingly, nuclear actin levels have also been described to contribute to the regulation of Hippo pathway (e.g.…”

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

“…However, it does not exclude other mechanisms and pathways that could sense apical membrane size, membrane tension, cell-cell junction integrity, and, in general, the actin cytoskeleton. For example, the MAL/SRF transcription factors are also suitable candidates since they respond to actin dynamics and regulate YAP/TAZ target genes (Foster et al, 2017). In addition, it remains unclear if nuclear receptors also signal through or affect the actin cytoskeleton and act in concert with the suggested acto-myosin-mediated signaling branch.…”

“…Hepatocytes were isolated and cultured as described in Godoy et al () and Zeigerer et al (), respectively. Cells were treated with 20 μM Y27, fasudil, SMIFH2, CK666, or 5 μM latrunculin A or cytochalasin D for 6 h. For BA experiments, cells were pre‐incubated with 20 μM Y27 or DMSO (control) for 1 h, followed by 16–18 h incubation with DMSO, 200 μM DCA, 20 μM Y27, or 20 μM + 200 μM DCA.…”

“…However, latrunculin A reduced YAP target gene expression despite increasing nuclear YAP levels, indicating that nuclear translocation is not sufficient for target gene expression in this system. This is not too surprising as these genes are subjected to a much more complex transcriptional regulation that can be actin-dependent (MAL/SRF, Foster et al, 2017) and thus affected by the inhibitor.…”