Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways.

Boon C Heng,Dominique Aubel,Yunyang Bai,Xiaochan Li,Xuliang Deng,Martin Fussenegger,Yan Wei,Xuehui Zhang

doi:10.3389/fcell.2020.00735

Abstract

The penultimate effectors of the Hippo signaling pathways YAP and TAZ, are transcriptional co-activator proteins that play key roles in many diverse biological processes, ranging from cell proliferation, tumorigenesis, mechanosensing and cell lineage fate determination, to wound healing and regeneration. In this review, we discuss the regulatory mechanisms by which YAP/TAZ control stem/progenitor cell differentiation into the various major lineages that are of interest to tissue engineering and regenerative medicine applications. Of particular interest is the key role of YAP/TAZ in maintaining the delicate balance between quiescence, self-renewal, proliferation and differentiation of endogenous adult stem cells within various tissues/organs during early development, normal homeostasis and regeneration/healing. Finally, we will consider how increasing knowledge of YAP/TAZ signaling might influence the trajectory of future progress in regenerative medicine.

Highlights

YAP (Yes-associated protein, known as YAP1) and TAZ are two homologous transcriptional co-activator proteins (Webb et al, 2011) (Figure 1), which shuttle between the cytosol and cell nuclei to regulate target gene expression via binding interactions with TEAD (TEA/ATTS domain) transcription factors (Lin et al, 2017b)
It must be noted that there are additional layers of complex mechanisms that modulate the effects of YAP/TAZ signaling via (i) factors that modulate YAP/TAZ binding to TEAD, such as P38 MAPK4 (Lin et al, 2017a) and VGLL4 (Zhang et al, 2014; Lin et al, 2016; Deng and Fang, 2018); (ii) methylation and phosphorylation of YAP/TAZ via SET7 (Oudhoff et al, 2013) and PTPN14 (Liu et al, 2013) respectively; and (iii) YAP/TAZ binding and modulation of various non-TEAD transcription factors, such as Smad2/3 (Grannas et al, 2015), Runx2 (Brusgard et al, 2015; Lin et al, 2019), p63 (Tomlinson et al, 2010), p73 (Roperch et al, 2008), PRDM4 (Liu et al, 2018), OCT4 and SOX2 (Bora-Singhal et al, 2015)
Despite the great interest in the roles of YAP/TAZ in cancer and tumorigenesis, as much attention, if not more, has been focused on how YAP/TAZ maintains the delicate balance between quiescence, self-renewal, proliferation and differentiation of endogenous adult stem cells in various different tissue types during the processes of tissue regeneration and healing

Summary

INTRODUCTION

YAP (Yes-associated protein, known as YAP1) and TAZ (transcriptional co-activator with PDZ-binding motif) are two homologous transcriptional co-activator proteins (Webb et al, 2011) (Figure 1), which shuttle between the cytosol (phosphorylated inactive state) and cell nuclei (unphosphorylated active state) to regulate target gene expression via binding interactions with TEAD (TEA/ATTS domain) transcription factors (Lin et al, 2017b). Components of the core Hippo signaling cascade (Figure 2) and other non-Hippo signaling pathways (Pocaterra et al, 2020) It is precisely this delicate balance of nuclear to cytoplasmic ratio of unphosphorylated and phosphorylated YAP/TAZ respectively, which plays such a crucial role in cell lineage fate determination (Figure 3); and in the activation and mobilization of endogenous stem/progenitor cells during the regeneration process following tissue/organ disease or injury (Figure 4). Findings with mouse ESCs may not necessarily be applicable to human ESCs. several studies have demonstrated that human ESCs exhibit elevated YAP/TAZ activity like mouse ESCs, which in turn plays a key role in their self-renewal, and maintenance of pluripotency and stem cell phenotype (Varelas et al, 2008; Musah et al, 2014; Ohgushi et al, 2015; Hsiao et al, 2016).

Key references

Rho GTPase

CONCLUSION AND FUTURE OUTLOOK

AUTHOR CONTRIBUTIONS