Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

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.

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

Biochemical Journal ◽

10.1042/bcj20180717 ◽

2019 ◽

Vol 476 (4) ◽

pp. 759-768 ◽

Cited By ~ 5

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.

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

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa052 ◽

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.

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

Cancers ◽

10.3390/cancers10030081 ◽

2018 ◽

Vol 10 (3) ◽

pp. 81 ◽

Cited By ~ 38

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.

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

Biology of Reproduction ◽

10.1093/biolre/ioz139 ◽

2019 ◽

Vol 101 (5) ◽

pp. 1001-1017 ◽

Cited By ~ 7

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.

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RHPCG: a database of the Regulation of the Hippo Pathway in Cancer Genome

Database ◽

10.1093/database/baz135 ◽

2019 ◽

Vol 2019 ◽

Cited By ~ 1

Author(s):

Chengyu Wang ◽

Fan Yang ◽

Tingting Chen ◽

Qi Dong ◽

Zhangxiang Zhao ◽

...

Keyword(s):

Signaling Pathway ◽

Hippo Pathway ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Hippo Signaling ◽

Protein Coding ◽

Hippo Signaling Pathway ◽

Cancer Genome Atlas ◽

Cancer Types ◽

The Hippo Pathway

Abstract The Hippo signaling pathway is a highly conserved pathway controlling organ size, cell proliferation, apoptosis and other biological functions. Recent studies have shown that Hippo signaling pathway also plays important roles in cancer initiation and progression. However, a database offering multi-omics analyses and visualization of Hippo pathway genes in cancer, as well as comprehensive Hippo regulatory relationships is still lacking. To fill this gap, we constructed the Regulation of the Hippo Pathway in Cancer Genome (RHPCG) database. Currently, RHPCG focuses on analyzing the 21 core Hippo-protein-encoding genes in over 10 000 patients across 33 TCGA (The Cancer Genome Atlas) cancer types at the levels of genomic, epigenomic and transcriptomic landscape. Concurrently, RHPCG provides in its motif section 11 regulatory motif types associated with 21 core Hippo pathway genes containing 180 miRNAs, 6182 lncRNAs, 728 circRNAs and 335 protein coding genes. Thus, RHPCG is a powerful tool that could help researchers understand gene alterations and regulatory mechanisms in the Hippo signaling pathway in cancer.

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Hippo Signaling Pathway in Gliomas

Cells ◽

10.3390/cells10010184 ◽

2021 ◽

Vol 10 (1) ◽

pp. 184

Author(s):

Konstantin Masliantsev ◽

Lucie Karayan-Tapon ◽

Pierre-Olivier Guichet

Keyword(s):

Brain Tumors ◽

Signaling Pathway ◽

Cancer Biology ◽

Nuclear Translocation ◽

Hippo Pathway ◽

Binding Motif ◽

Hippo Signaling ◽

Central Nervous System Neoplasms ◽

Hippo Signaling Pathway

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.

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Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00077.2014 ◽

2014 ◽

Vol 307 (2) ◽

pp. G196-G204 ◽

Cited By ~ 88

Author(s):

James L. Grijalva ◽

Megan Huizenga ◽

Kaly Mueller ◽

Steven Rodriguez ◽

Joseph Brazzo ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Liver Regeneration ◽

Signaling Pathway ◽

Target Gene ◽

Hippo Pathway ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Target Gene Expression ◽

The Hippo Pathway

The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liver-to-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.

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POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1715165115 ◽

2018 ◽

Vol 115 (9) ◽

pp. 2150-2155 ◽

Cited By ~ 10

Author(s):

Xianjue Ma ◽

Xiaowei Guo ◽

Helena E. Richardson ◽

Tian Xu ◽

Lei Xue

Keyword(s):

Target Genes ◽

Hippo Pathway ◽

Physiological Role ◽

Cell Renewal ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Stem Cell Renewal ◽

The Hippo Pathway ◽

Precise Molecular Mechanism

The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in Drosophila. POSH overexpression synergizes with loss of Kibra to induce overgrowth and up-regulation of Hippo pathway target genes. Furthermore, knockdown of POSH impedes dextran sulfate sodium-induced Yorkie-dependent intestinal stem cell renewal, suggesting a physiological role of POSH in modulating Hippo signaling. Mechanistically, POSH binds to the C-terminal of Ex and is essential for the Crumbs-induced ubiquitination and degradation of Ex. Our findings establish POSH as a crucial regulator that integrates the signal from the cell surface to negatively regulate Ex-mediated Hippo activation in Drosophila.

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Mechanotransduction and Cytoskeleton Remodeling Shaping YAP1 in Gastric Tumorigenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20071576 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1576 ◽

Cited By ~ 4

Author(s):

Jinglin Zhang ◽

Yuhang Zhou ◽

Patrick Tang ◽

Alfred Cheng ◽

Jun Yu ◽

...

Keyword(s):

Hippo Pathway ◽

Tumor Formation ◽

Binding Motif ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Therapeutic Value ◽

Cytoskeleton Remodeling ◽

Mechanical Sensor ◽

The Hippo Pathway

The essential role of Hippo signaling pathway in cancer development has been elucidated by recent studies. In the gastrointestinal tissues, deregulation of the Hippo pathway is one of the most important driving events for tumorigenesis. It is widely known that Yes-associated protein 1 (YAP1) and WW domain that contain transcription regulator 1 (TAZ), two transcriptional co-activators with a PDZ-binding motif, function as critical effectors negatively regulated by the Hippo pathway. Previous studies indicate the involvement of YAP1/TAZ in mechanotransduction by crosstalking with the extracellular matrix (ECM) and the F-actin cytoskeleton associated signaling network. In gastric cancer (GC), YAP1/TAZ functions as an oncogene and transcriptionally promotes tumor formation by cooperating with TEAD transcription factors. Apart from the classic role of Hippo-YAP1 cascade, in this review, we summarize the current investigations to highlight the prominent role of YAP1/TAZ as a mechanical sensor and responder under mechanical stress and address its potential prognostic and therapeutic value in GC.

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The Human Adenovirus Type 5 E4orf4 Protein Targets Two Phosphatase Regulators of the Hippo Signaling Pathway

Journal of Virology ◽

10.1128/jvi.03710-14 ◽

2015 ◽

Vol 89 (17) ◽

pp. 8855-8870 ◽

Cited By ~ 6

Author(s):

Melissa Z. Mui ◽

Yiwang Zhou ◽

Paola Blanchette ◽

Naila Chughtai ◽

Jennifer F. Knight ◽

...

Keyword(s):

Tumor Cell ◽

Signaling Pathway ◽

Human Cancer ◽

Affinity Purification ◽

Hippo Pathway ◽

Human Adenovirus ◽

Mass Spectrometry Analysis ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

The Hippo Pathway

ABSTRACTWhen expressed alone at high levels, the human adenovirus E4orf4 protein exhibits tumor cell-specific p53-independent toxicity. A major E4orf4 target is the B55 class of PP2A regulatory subunits, and we have shown recently that binding of E4orf4 inhibits PP2AB55phosphatase activity in a dose-dependent fashion by preventing access of substrates (M. Z. Mui et al., PLoS Pathog 9:e1003742, 2013,http://dx.doi.org/10.1371/journal.ppat.1003742). While interaction with B55 subunits is essential for toxicity, E4orf4 mutants exist that, despite binding B55 at high levels, are defective in cell killing, suggesting that other essential targets exist. In an attempt to identify additional targets, we undertook a proteomics approach to characterize E4orf4-interacting proteins. Our findings indicated that, in addition to PP2AB55subunits, ASPP-PP1 complex subunits were found among the major E4orf4-binding species. Both the PP2A and ASPP-PP1 phosphatases are known to positively regulate effectors of the Hippo signaling pathway, which controls the expression of cell growth/survival genes by dephosphorylating the YAP transcriptional coactivator. We find here that expression of E4orf4 results in hyperphosphorylation of YAP, suggesting that Hippo signaling is affected by E4orf4 interactions with PP2AB55and/or ASPP-PP1 phosphatases. Furthermore, knockdown of YAP1 expression was seen to enhance E4orf4 killing, again consistent with a link between E4orf4 toxicity and inhibition of the Hippo pathway. This effect may in fact contribute to the cancer cell specificity of E4orf4 toxicity, as many human cancer cells rely heavily on the Hippo pathway for their enhanced proliferation.IMPORTANCEThe human adenovirus E4orf4 protein has been known for some time to induce tumor cell-specific death when expressed at high levels; thus, knowledge of its mode of action could be of importance for development of new cancer therapies. Although the B55 form of the phosphatase PP2A has long been known as an essential E4orf4 target, genetic analyses indicated that others must exist. To identify additional E4orf4 targets, we performed, for the first time, a large-scale affinity purification/mass spectrometry analysis of E4orf4 binding partners. Several additional candidates were detected, including key regulators of the Hippo signaling pathway, which enhances cell viability in many cancers, and results of preliminary studies suggested a link between inhibition of Hippo signaling and E4orf4 toxicity.

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