Myocardin-Related Transcription Factor A and Yes-Associated Protein Exert Dual Control in G Protein-Coupled Receptor- and RhoA-Mediated Transcriptional Regulation and Cell Proliferation

Abstract

The ability of a subset of G-protein coupled receptors (GPCRs) to activate RhoA endows them with unique growth regulatory properties. Two transcriptional pathways are activated through GPCRs and RhoA, one utilizing SRF and its transcriptional co-activator MRTF-A, the other, TEAD and its transcriptional co-activator YAP. These pathways have not been compared for their relative importance and potential interactions in RhoA target gene expression. GPCRs for thrombin and S1P on human glioblastoma cells robustly couple to RhoA and induce the matricelluar protein CCN1. Knockdown of either MRTF-A or YAP abrogates S1P stimulated CCN1 expression, demonstrating that both co-activators are required. MRTF-A and YAP are also both required for induction of other S1P regulated genes in various cell types and for S1P stimulated glioblastoma cell proliferation. Interactions between MRTF-A and YAP are indicated by their synergistic effects on SRE.L and TEAD-luciferase expression. Moreover, MRTF-A and YAP associate in co-IPs from S1P stimulated cells. ChIP analysis of the CCN1 promoter demonstrates that S1P increases co-activator binding at their canonical transcription factor sequences. Unexpectedly, SIP also enhances MRTF-A binding at TEA sites. Our findings reveal that GPCR and RhoA-regulated gene expression requires dual input and integration of two distinct transcriptional pathways.

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

“…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.…”

“…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.…”

“…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). …”

Regulation of Myocardial Cell Growth and Death by the Hippo Pathway

“…26 Yap also interacts with myocardin-related transcription factor A (MRTA), a transcription cofactor, in response to sphingosine-1-phosphate, thereby positively regulating transcription of CYR61 through cooperative actions between the Yap-TEAD pathway and the MRTA-serum response factor pathway. 27 ubiquitin proteasome system. 14 When the Hippo pathway is inactivated, Yap translocates to the nucleus and interacts with multiple transcription factors, including the TEAD/TEF family transcription factors.…”

A growing role for the Hippo signaling pathway in the heart

“…Lacking the ability to bind directly to DNA, nuclear YAP/TAZ associate with numerous transcription factors to modulate gene expression. Partners of YAP/TAZ include MRTF-A[23], FoxO1[24], Tbx5[25, 26], Runx[27, 28], p73[29], Smads[30, 31], and TEADs among others[32]. YAP/TAZ have been shown to regulate expression of genes that promote cell proliferation, survival and metabolic function.…”