scholarly journals Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Cancers ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 81 ◽  
Author(s):  
◽  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Therapeutic Potential ◽  
Hippo Pathway ◽  
Large Body ◽  
Hippo Signaling ◽  
Wide Range ◽  
The Hippo Pathway

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

scholarly journals Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2438 ◽  
Author(s):  
Sahar Sarmasti Emami ◽  
Derek Zhang ◽  
Xiaolong Yang
Keyword(s):  
Signaling Pathway ◽  
Hippo Pathway ◽  
Underlying Mechanism ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Cellular Processes ◽  
Wide Range ◽  
Future Direction ◽  
The Hippo Pathway

The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

Drosophila Hcf regulates the Hippo signaling pathway via association with the histone H3K4 methyltransferase Trr

2019 ◽  
Vol 476 (4) ◽  
pp. 759-768 ◽  
Author(s):  
Zi Nan ◽  
Weiwei Yang ◽  
Jialan Lyu ◽  
Fang Wang ◽  
Qiannan Deng ◽  
...  
Keyword(s):  
Host Cell ◽  
Signaling Pathway ◽  
Hippo Pathway ◽  
Organ Size ◽  
Fundamental Aspect ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Host Cell Factor ◽  
Histone H3k4 ◽  
The Hippo Pathway

Abstract Control of organ size is a fundamental aspect in biology and plays important roles in development. The Hippo pathway is a conserved signaling cascade that controls tissue and organ size through the regulation of cell proliferation and apoptosis. Here, we report on the roles of Hcf (host cell factor), the Drosophila homolog of Host cell factor 1, in regulating the Hippo signaling pathway. Loss-of-Hcf function causes tissue undergrowth and the down-regulation of Hippo target gene expression. Genetic analysis reveals that Hcf is required for Hippo pathway-mediated overgrowth. Mechanistically, we show that Hcf associates with the histone H3 lysine-4 methyltransferase Trithorax-related (Trr) to maintain H3K4 mono- and trimethylation. Thus, we conclude that Hcf positively regulates Hippo pathway activity through forming a complex with Trr and controlling H3K4 methylation.

scholarly journals A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

2020 ◽  
Vol 26 (9) ◽  
pp. 653-664
Author(s):  
Challis Karasek ◽  
Mohamed Ashry ◽  
Chad S Driscoll ◽  
Jason G Knott
Keyword(s):  
Signaling Pathway ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cell Mass ◽  
Preimplantation Embryos ◽  
Hippo Signaling ◽  
Cell Fate Decisions ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway

Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

scholarly journals α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

2021 ◽  
Vol 134 (8) ◽  
Author(s):  
Aleena K. S. Arakaki ◽  
Wen-An Pan ◽  
Helen Wedegaertner ◽  
Ivette Roca-Mercado ◽  
Logan Chinn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
The Hippo Pathway

ABSTRACT The α-arrestin domain containing protein 3 (ARRDC3) is a tumor suppressor in triple-negative breast carcinoma (TNBC), a highly metastatic subtype of breast cancer that lacks targeted therapies. Thus, understanding the mechanisms and targets of ARRDC3 in TNBC is important. ARRDC3 regulates trafficking of protease-activated receptor 1 (PAR1, also known as F2R), a G-protein-coupled receptor (GPCR) implicated in breast cancer metastasis. Loss of ARRDC3 causes overexpression of PAR1 and aberrant signaling. Moreover, dysregulation of GPCR-induced Hippo signaling is associated with breast cancer progression. However, the mechanisms responsible for Hippo dysregulation remain unknown. Here, we report that the Hippo pathway transcriptional co-activator TAZ (also known as WWTR1) is the major effector of GPCR signaling and is required for TNBC migration and invasion. Additionally, ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, which occurs independently of ARRDC3-regulated PAR1 trafficking. The ARRDC3 C-terminal PPXY motifs and TAZ WW domain are crucial for this interaction and are required for suppression of TNBC migration and lung metastasis in vivo. These studies are the first to demonstrate a role for ARRDC3 in regulating GPCR-induced TAZ activity in TNBC and reveal multi-faceted tumor suppressor functions of ARRDC3. This article has an associated First Person interview with the first author of the paper.

scholarly journals Usp10 Modulates the Hippo Pathway by Deubiquitinating and Stabilizing the Transcriptional Coactivator Yorkie

2019 ◽  
Vol 20 (23) ◽  
pp. 6013
Author(s):  
Yang Gao ◽  
Xiaoting Zhang ◽  
Lijuan Xiao ◽  
Chaojun Zhai ◽  
Tao Yi ◽  
...  
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Size Control ◽  
Deubiquitinating Enzyme ◽  
Hippo Signaling ◽  
Evolutionarily Conserved ◽  
Specific Protease ◽  
Wing Discs ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved regulator that plays important roles in organ size control, homeostasis, and tumorigenesis. As the key effector of the Hippo pathway, Yorkie (Yki) binds to transcription factor Scalloped (Sd) and promotes the expression of target genes, leading to cell proliferation and inhibition of apoptosis. Thus, it is of great significance to understand the regulatory mechanism for Yki protein turnover. Here, we provide evidence that the deubiquitinating enzyme ubiquitin-specific protease 10 (Usp10) binds Yki to counteract Yki ubiquitination and stabilize Yki protein in Drosophila S2 cells. The results in Drosophila wing discs indicate that silence of Usp10 decreases the transcription of target genes of the Hippo pathway by reducing Yki protein. In vivo functional analysis ulteriorly showed that Usp10 upregulates the Yki activity in Drosophila eyes. These findings uncover Usp10 as a novel Hippo pathway modulator and provide a new insight into the regulation of Yki protein stability and activity.

scholarly journals A new perspective on the evolution of the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors

2020 ◽  
Author(s):  
Yannick Mesrouze ◽  
Gustavo Aguilar ◽  
Fedir Bokhovchuk ◽  
Typhaine Martin ◽  
Clara Delaunay ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Hippo Pathway ◽  
Structural Difference ◽  
Amino Acid Motif ◽  
Structural Element ◽  
Genome Wide ◽  
Transcriptional Cofactors ◽  
New Perspective ◽  
The Hippo Pathway

AbstractThe most downstream elements of the Hippo pathway, the TEAD transcription factors, are regulated by several cofactors, such as Vg/VGLL1-3. Earlier findings on human VGLL1 and here on human VGLL3 show that these proteins interact with TEAD via a conserved amino acid motif called the TONDU domain. Surprisingly, our studies reveal that the TEAD-binding domain of Drosophila Vg and of human VGLL2 is more complex and contains an additional structural element, an Ω-loop, that contributes to TEAD binding and in vivo function. To explain this unexpected structural difference between proteins from the same family, we propose that, after the genome-wide duplications at the origin of vertebrates, the Ω-loop present in an ancestral VGLL gene has been lost in some VGLL variants. These findings illustrate how structural and functional constraints can guide the evolution of transcriptional cofactors to preserve their ability to compete with other cofactors for binding to transcription factors.

scholarly journals GPCR-Hippo Signaling in Cancer

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 426 ◽  
Author(s):  
Jiaqian Luo ◽  
Fa-Xing Yu
Keyword(s):  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Cancer Therapies ◽  
Aberrant Expression ◽  
Wide Range ◽  
Anti Cancer ◽  
Genetic Deletion ◽  
The Hippo Pathway ◽  
G Protein Coupled

The Hippo signaling pathway is involved in tissue size regulation and tumorigenesis. Genetic deletion or aberrant expression of some Hippo pathway genes lead to enhanced cell proliferation, tumorigenesis, and cancer metastasis. Recently, multiple studies have identified a wide range of upstream regulators of the Hippo pathway, including mechanical cues and ligands of G protein-coupled receptors (GPCRs). Through the activation related G proteins and possibly rearrangements of actin cytoskeleton, GPCR signaling can potently modulate the phosphorylation states and activity of YAP and TAZ, two homologous oncogenic transcriptional co-activators, and major effectors of the Hippo pathway. Herein, we summarize the network, regulation, and functions of GPCR-Hippo signaling, and we will also discuss potential anti-cancer therapies targeting GPCR-YAP signaling.

scholarly journals Yes-associated protein 1 is required for proliferation and function of bovine granulosa cells in vitro†

2019 ◽  
Vol 101 (5) ◽  
pp. 1001-1017 ◽  
Author(s):  
Michele R Plewes ◽  
Xiaoying Hou ◽  
Pan Zhang ◽  
Aixin Liang ◽  
Guohua Hua ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Localization ◽  
Granulosa Cells ◽  
Hippo Pathway ◽  
Critical Role ◽  
Small Cells ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway

Abstract Yes-associated protein 1 (YAP1) is a major component of the Hippo signaling pathway. Although the exact extracellular signals that control the Hippo pathway are currently unknown, increasing evidence supports a critical role for the Hippo pathway in embryonic development, regulation of organ size, and carcinogenesis. Granulosa cells (GCs) within the ovarian follicle proliferate and produce steroids and growth factors, which facilitate the growth of follicle and maturation of the oocyte. We hypothesize that YAP1 plays a role in proliferation and estrogen secretion of GCs. In the current study, we examined the expression of the Hippo signaling pathway in bovine ovaries and determined whether it was important for GC proliferation and estrogen production. Mammalian STE20-like protein kinase 1 (MST1) and large tumor suppressor kinase 2 (LATS2) were identified as prominent upstream components of the Hippo pathway expressed in granulosa and theca cells of the follicle and large and small cells of the corpus luteum. Immunohistochemistry revealed that YAP1 was localized to the nucleus of growing follicles. In vitro, nuclear localization of the downstream Hippo signaling effector proteins YAP1 and transcriptional co-activator with PDZ-binding motif (TAZ) was inversely correlated with GC density, with greater nuclear localization under conditions of low cell density. Treatment with verteporfin and siRNA targeting YAP1 or TAZ revealed a critical role for these transcriptional co-activators in GC proliferation. Furthermore, knockdown of YAP1 in GCs inhibited follicle-stimulating hormone (FSH)-induced estradiol biosynthesis. The data indicate that Hippo pathway transcription co-activators YAP1/TAZ play an important role in GC proliferation and estradiol synthesis, two processes necessary for maintaining normal follicle development.

scholarly journals Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vikrant Borse ◽  
Matthew Barton ◽  
Harry Arndt ◽  
Tejbeer Kaur ◽  
Mark E. Warchol
Keyword(s):  
Inner Ear ◽  
Cellular Localization ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Supporting Cells ◽  
The Hippo Pathway

AbstractThe Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear.

scholarly journals Apoptosis in Type 2 Diabetes, Can It be Prevented?

2021 ◽  
Author(s):  
Agnieszka Kilanowska ◽  
Agnieszka Ziółkowska
Keyword(s):  
Beta Cells ◽  
Hippo Pathway ◽  
Basic Research ◽  
Beta Cell Apoptosis ◽  
Hippo Signaling ◽  
Core Proteins ◽  
Wide Range ◽  
Potential Strategy ◽  
Apoptotic Pathways ◽  
The Hippo Pathway

Diabetes mellitus is a heterogeneous disease of complex etiology and pathogenesis. Hyperglycemia leads to many serious complications, but also directly initiates the process of β cell apoptosis. A potential strategy for the preservation of pancreatic β cells in diabetes may be to inhibit the implementation of pro-apoptotic pathways or to enhance the action of pancreatic protective factors. The HIPPO signaling pathway is proposed and selected as a target to manipulate the activity of its core proteins in therapy - basic research. MST1 and LATS2 as major upstream signaling kinases of the Hippo pathway are considered as target candidates for pharmacologically induced tissue regeneration and inhibition of apoptosis. Manipulating the activity of components of the HiPPO pathway offers a wide range of possibilities, and thus is a potential tool in the treatment of diabetes and the regeneration of β cells. Therefore, it is important to fully understand the processes involved in apoptosis in diabetic states and to fully characterize the role of this pathway in diabetes. Therapy consisting in slowing down or stopping the mechanisms of apoptosis may be an important direction of diabetes treatment shortly.

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