A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition

Abstract

Endothelial-to-mesenchymal transition (EndMT) is the biological process through which endothelial cells transdifferentiate into mesenchymal cells. During embryo development, EndMT regulates endocardial cushion formation via TGFβ/BMP signaling. In adults, EndMT is mainly activated during pathological conditions. Hence, it is necessary to characterize molecular regulators cooperating with TGFβ signaling in driving EndMT, to identify potential novel therapeutic targets to treat these pathologies. Here, we studied YAP, a transcriptional co-regulator involved in several biological processes, including epithelial-to-mesenchymal transition (EMT). As EndMT is the endothelial-specific form of EMT, and YAP (herein referring to YAP1) and TGFβ signaling cross-talk in other contexts, we hypothesized that YAP contributes to EndMT by modulating TGFβ signaling. We demonstrate that YAP is required to trigger TGFβ-induced EndMT response, specifically contributing to SMAD3-driven EndMT early gene transcription. We provide novel evidence that YAP acts as SMAD3 transcriptional co-factor and prevents GSK3β-mediated SMAD3 phosphorylation, thus protecting SMAD3 from degradation. YAP is therefore emerging as a possible candidate target to inhibit pathological TGFβ-induced EndMT at early stages.

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

“…It has been shown that YAP can prevent GSK3β-mediated Smad3 degradation, thereby promoting Smad3-induced EMT. 366 Furthermore, YAP is physically associated with β-catenin to form a transcriptional complex with TEAD4 in nucleus, leading to the overexpression of EMT-TFs including Slug and Twist in breast cancer. 367 It is worth noting that TEAD4 can regulate EMT and promote metastasis by directly transcribing vimentin without the binding with YAP in colorectal cancer, which is interesting.…”

“…Moreover, Hippo signaling can be cross‐linked with other developmental pathways, such as TGFβ and Wnt, to coordinate EMT program. It has been shown that YAP can prevent GSK3β‐mediated Smad3 degradation, thereby promoting Smad3‐induced EMT 366 . Furthermore, YAP is physically associated with β‐catenin to form a transcriptional complex with TEAD4 in nucleus, leading to the overexpression of EMT‐TFs including Slug and Twist in breast cancer 367 .…”

In the spotlight: the role of TGFβ signalling in haematopoietic stem and progenitor cell emergence

“…Chromatin binding data for the individual Smad proteins in HE or HSPC/HSCs would be desirable, but will remain a challenge to perform in low cell number samples until good antibodies and new alternatives to conventional ChIP such as Cut&Tag [ 78 ] are standardised. Moreover, Smad proteins only bind to DNA transiently and need transcription factors to stabilise these interactions that additionally increases the difficulty in identifying bona fide binding targets [ 60 , 79 ]. Finally, there is still a need to develop specific compounds to activate or inhibit specific TGFβ receptors and ligands since TGFβ signalling is aberrantly expressed in many diseases [ 80 ].…”

“…A more complex function for SMAD2/3 in EHT can be anticipated from studies on EndoMT. In EndoMT, the Hippo pathway member YAP1 can compete with Smad4 for complex formation with Smad3 during cardiac cushion formation [ 60 ]. The study finds that YAP1/Smad3 complexes have a stronger DNA binding affinity and drive stable transcription of downstream targets [ 60 ].…”

“…In EndoMT, the Hippo pathway member YAP1 can compete with Smad4 for complex formation with Smad3 during cardiac cushion formation [ 60 ]. The study finds that YAP1/Smad3 complexes have a stronger DNA binding affinity and drive stable transcription of downstream targets [ 60 ]. It´s noteworthy that YAP1 induced by shear stress is required for HSPC/HSC maintenance in the zebrafish AGM [ 61 ].…”