MRTF potentiates TEAD‐YAP transcriptional activity causing metastasis

Abstract

Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical extracellular cues. The mechanism underlying this crosstalk, however, remains 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 and breast cancer metastasis to the lung We also demonstrate the significance of MRTF-YAP binding in regulation of YAP activity upon acute actin cytoskeletal damage. Acute actin disruption induces nucleo-cytoplasmic shuttling of MRTF, and this process underlies 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. Our results also suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP.

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

“…Recent experiments have demonstrated direct physical interactions between the YAP/TAZ WW domain and a conserved PPxY motif at the C terminus of myocardin family proteins, including the MRTFs (Speight et al 2016;Yu et al 2016;Kim et al 2017). Our experiments with constitutively activated MRTF and YAP suggest that these interactions do not directly contribute to the transactivating functions of MRTF.…”

“…Recent studies have demonstrated physical interaction between MRTF and YAP independent of their DNA-binding cofactor proteins, SRF and TEAD (Speight et al 2016;Yu et al 2016;Kim et al 2017). The ChIP data presented above and the fact that YAP-TEAD and MRTF-SRF ChIPseq data exhibit only partial overlap suggest that YAP-MRTF interaction is not sufficient to explain the mutual dependence of the two systems.…”

“…Some genes, such as Ctgf, Cyr61, and Ankrd1, contain binding sites for both SRF and TEAD and thus represent shared targets (for example, see Latinkic et al 1991;Zhang et al 2011). Moreover, YAP/TAZ and the MRTFs can physically interact, although it remains unclear whether this allows their recruitment to DNA independently of their own DNAbinding partners (Speight et al 2016;Yu et al 2016;Kim et al 2017). …”

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

“…To date, it is only known that MRTF and YAP are both mandatory for vascular development. However, the question of whether these two mechanoresponsive signaling pathways are redundant backup systems or whether they, at least partially, collaborate (Yu et al, 2015;Kim et al, 2016) remained open.…”

“…Most important, the abundance of shared MRTF and YAP target genes gives rise to the question of whether their regulation during vascular development is tightly correlated or if they act in a partially redundant manner. Addressing these questions will contribute to an improved understanding of the recently suggested functional relation between SRF and Hippo signaling (Kim et al, 2016;Speight et al, 2016), not only in angiogenesis, but also in cancer development and its progression in general.…”