Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Aug 9;4(4):e340.
doi: 10.1002/mco2.340. eCollection 2023 Aug.

YAP/TAZ: Molecular pathway and disease therapy

Yuzi Wei  1 , Victoria Lee Zhi Hui  1 , Yilin Chen  1   2 , Ruiying Han  1   2 , Xianglong Han  1   2 , Yongwen Guo  1   2   3
Affiliations
Review

YAP/TAZ: Molecular pathway and disease therapy

Yuzi Wei et al. MedComm (2020). .

Abstract

The Yes-associated protein and its transcriptional coactivator with PDZ-binding motif (YAP/TAZ) are two homologous transcriptional coactivators that lie at the center of a key regulatory network of Hippo, Wnt, GPCR, estrogen, mechanical, and metabolism signaling. YAP/TAZ influences the expressions of downstream genes and proteins as well as enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, and the transdifferentiation of fibroblasts into myofibroblasts. YAP/TAZ can also be regulated through epigenetic regulation and posttranslational modifications. Consequently, the regulatory function of these mechanisms implicates YAP/TAZ in the pathogenesis of metabolism-related diseases, atherosclerosis, fibrosis, and the delicate equilibrium between cancer progression and organ regeneration. As such, there arises a pressing need for thorough investigation of YAP/TAZ in clinical settings. In this paper, we aim to elucidate the signaling pathways that regulate YAP/TAZ and explore the mechanisms of YAP/TAZ-induce diseases and their potential therapeutic interventions. Furthermore, we summarize the current clinical studies investigating treatments targeting YAP/TAZ. We also address the limitations of existing research on YAP/TAZ and propose future directions for research. In conclusion, this review aims to provide fresh insights into the signaling mediated by YAP/TAZ and identify potential therapeutic targets to present innovative solutions to overcome the challenges associated with YAP/TAZ.

Keywords: YAP/TAZ; atherosclerosis; cancer; fibrosis; metabolism; regeneration.

PubMed Disclaimer

Conflict of interest statement

There is no conflict of interest for all the authors.

Figures

FIGURE 1
FIGURE 1
The structure of YAP/TAZ. At the N‐terminal, YAP/TAZ all have a TEAD binding region and all have a transcription activation domain at the C‐terminal, including PDZ binding and Coiled‐coil region. Comparing with the TAZ, the YAP also has a SH3 binding region and YAP2 has one more WW domain.
FIGURE 2
FIGURE 2
The main signaling pathways of YAP/TAZ. YAP/TAZ can be regulated by Hippo signaling, Wnt signaling, GPCR signaling, estrogen signaling, and mechanical signaling. In the Hippo signaling pathway, the phosphorylated MST1/2 interacts with SAV1 to phosphorylate and activate the LATS1/2, then the activated LAST1/2 phosphorylates and inhibits YAP/TAZ. Wnt signaling has two pathways to regulate the YAP/TAZ. One way is to activate YAP/TAZ through LATS1/2 inhibited by Rho while the other is to modulate YAP/TAZ by β‐catenin complex. And the regulations of GPCR signaling and Estrogen signaling are almost similar as the previous one of Wnt signaling. YAP/TAZ can serve as mechanotransduction to participant in mechanical signaling. Under the stimuli of FA, YAP/TAZ is regulated through two Hippo‐dependent pathways: β1‐integrin–FAK–SRC–PI3K–PDK1 signaling pathway and the β1‐integrin–FAK–P130–Cas–Rac1–PAK–Merlin pathway. In the Hippo‐independent pathway, mechanical signaling is transmitted to the nucleus mediated by stress fiber. The unphosphorylated and uninhibited YAP/TAZ is able to proceed the nuclear translocation.
FIGURE 3
FIGURE 3
The mechanisms of YAP in metabolism. YAP plays a significant role in glucose, amino acid, and nucleotide metabolism. In glucose metabolism, not only glucose transporters but also enzymes in glycolysis can be regulated by YAP directly or indirectly. And YAP can also modulate amino acid metabolism by regulating transporters. As for glutamic acid (Glu), in one hand, YAP promotes its transformation into AKG, which is a part of tricarboxylic acid cycle through activating GOT1 and PSAT1. In another, YAP can also modulate GLUL to convert Glu to glutamine (Gln), thereby entering nucleotide synthesis.
FIGURE 4
FIGURE 4
YAP/TAZ participants in cancer cell growth and anticancer drugs resistance. YAP/TAZ participants in the developments of cancers, including liver cancer, lung cancer, and breast cancer. The activation of YAP can lead to cancer cell uncontrolled proliferation and cancer cells becoming insensitive to anticancer drugs.
FIGURE 5
FIGURE 5
YAP/TAZ influences the transition of normal artery and atherosclerosis. In endothelial cell and macrophage, YAP/TAZ can be activated through diverse upstream signals to promote the expression of proinflammatory genes and the release of inflammatory factors, finally leading to atherosclerosis. Besides, methotretin, Sal‐B, and naringin have been demonstrated that play a role in inhibiting YAP/TAZ to improve atherosclerosis.
FIGURE 6
FIGURE 6
The role of YAP/TAZ in fibrosis development and antifibrosis drugs targeting YAP/TAZ and Hippo signaling pathway. Many upstream signals can activate YAP/TAZ directly or inhibit Hippo signaling pathway to stimulate the transdifferentiation of fibroblast into myofibroblast and cause ECM deposition, finally resulting in aggravation of fibrosis. Notably, not only western drugs but also traditional Chinese medicines are widely used in antifibrosis therapy, which can inhibit the activation of YAP/TAZ or promote YAP/TAZ degradation.
FIGURE 7
FIGURE 7
Different mechanisms of YAP/TAZ in organ regeneration. In heart, intestinal, liver, YAP/TAZ can be activated through Hippo‐dependent and Hippo‐independent way and then promotes the pro‐proliferation genes expression to stimulate cell proliferation, which contributes to heart, intestinal, and liver regeneration. And in bone, YAP/TAZ has an effect on cartilage regeneration and bone remodeling through regulating osteocyte, osteoblast, osteoclast, and chondrocyte.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Nguyen CDK, Yi C. YAP/TAZ signaling and resistance to cancer therapy. Trends Cancer. 2019;5(5):283–296. - PMC - PubMed
    1. Rodrigues‐Pousada C, Devaux F, Caetano SM, et al. Yeast AP‐1 like transcription factors (Yap) and stress response: a current overview. Microb Cell. 2019;6(6):267–285. - PMC - PubMed
    1. Webb C, Upadhyay A, Giuntini F, et al. Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway. Biochemistry. 2011;50(16):3300–3309. - PubMed
    1. Zhou A, Yu H, Liu J, et al. Role of Hippo‐YAP signaling in osseointegration by regulating osteogenesis, angiogenesis, and osteoimmunology. Front Cell Dev Biol. 2020;8:780. - PMC - PubMed
    1. Kim Y, Jho E. Regulation of the Hippo signaling pathway by ubiquitin modification. BMB Rep. 2018;51(3):143–150. - PMC - PubMed