MRTF activates TEAD-YAP target gene expression

Yes Associated Protein (YAP) and Myocardin Related Transcription Factor (MRTF) play similar roles and crosstalk in directing the transcriptional responses to chemical and physical extracellular cues. However the mechanism by which the two proteins crosstalk has been unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD-YAP transcriptional complex and potentiate its transcriptional activity. We show this interaction of MRTF and YAP is critical for LPA-induced cancer cell invasion in vitro and breast cancer metastasis to the lung in vivo. We also demonstrate the significance of MRTF-YAP binding in mechanotransduction by showing that the nucleo-cytoplasmic shuttling of MRTF induced by changes in the actin cytoskeleton constitutes the LATS-independent regulation of YAP activity. Our results provide clear evidence of crosstalk between MRTF and YAP independent of the LATS kinases that normally act upstream of YAP signaling and suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP. Overall design: To examine the impact of MRTFB overexpression on TEAD-YAP target genes, we overexpressed G-actin binding deficient MRTFB mutants (MRTFB dN) that are otherwise wildtype, YAP binding deficient (dPY), SRF binding deficient (YA), both-binding deficient (YA/dPY) in MCF-10A cells by retroviral infection and performed RNA sequencing experiment. We were able to identify genes whose expressions are activated by MRTFB overexpression, and genes whose expressions are depedent on MRTF-YAP or MRTF-SRF binding.