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1
Matthaios, Dimitrios, Maria Tolia, Davide Mauri, Konstantinos Kamposioras, and Michalis Karamouzis. "YAP/Hippo Pathway and Cancer Immunity: It Takes Two to Tango." Biomedicines 9, no. 12 (December 20, 2021): 1949. http://dx.doi.org/10.3390/biomedicines9121949.
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Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series of effects: extracellular vesicles enhanced immunity through inhibition of LATS1/2, ways of modulation of the tumor microenvironment, YAP- and TAZ-mediated upregulation of PDL1, high expression of YAP and PDL1 in EGFR-TKI-resistant cells, enhanced YAP activity in inflammation, and the effect of the Hippo pathway on T cells, B cells, Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs). These pleiotropic effects render the YAP and Hippo pathway a key pathway for exploitation in the future, in order to enhance our immunotherapy treatment strategies in oncology.
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Salem and Hansen. "The Hippo Pathway in Prostate Cancer." Cells 8, no. 4 (April 23, 2019): 370. http://dx.doi.org/10.3390/cells8040370.
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Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors—the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)—are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa.
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Agarinis, C., V. Orsini, P. Megel, Y. Abraham, H. Yang, C. Mickanin, V. Myer, T. Bouwmeester, J. S. Tchorz, and C. N. Parker. "Activation of Yap-Directed Transcription by Knockdown of Conserved Cellular Functions." Journal of Biomolecular Screening 21, no. 3 (December 2, 2015): 269–76. http://dx.doi.org/10.1177/1087057115617906.
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The Yap-Hippo pathway has a significant role in regulating cell proliferation and growth, thus controlling organ size and regeneration. The Hippo pathway regulates two highly conserved, transcription coactivators, YAP and TAZ. The upstream regulators of the Yap-Hippo pathway have not been fully characterized. The aim of this study was to use a siRNA screen, in a liver biliary cell line, to identify regulators of the Yap-Hippo pathway that allow activation of the YAP transcription coactivator at high cell density. Activation of the YAP transcription coactivator was monitored using a high-content, image-based assay that measured the intracellular localization of native YAP protein. Active siRNAs were identified and further validated by quantification of CYR61 mRNA levels (a known YAP target gene). The effect of compounds targeting the putative gene targets identified as hits was also used for further validation. A number of validated hits reveal basic aspects of Yap-Hippo biology, such as components of the nuclear pore, by which YAP cytoplasmic–nuclear shuttling occurs, or how proteasomal degradation regulates intracellular YAP concentrations, which then alter YAP localization and transcription. Such results highlight how targeting conserved cellular functions can lead to validated activity in phenotypic assays.
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Grijalva, James L., Megan Huizenga, Kaly Mueller, Steven Rodriguez, Joseph Brazzo, Fernando Camargo, Ghazaleh Sadri-Vakili, and Khashayar Vakili. "Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 2 (July 15, 2014): G196—G204. http://dx.doi.org/10.1152/ajpgi.00077.2014.
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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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Yang, Haitang, Sean R. R. Hall, Beibei Sun, Liang Zhao, Yanyun Gao, Ralph A. Schmid, Swee T. Tan, Ren-Wang Peng, and Feng Yao. "NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma." Cancers 13, no. 7 (March 29, 2021): 1561. http://dx.doi.org/10.3390/cancers13071561.
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(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.
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Huang, Shiyuan, Xiaona Wang, Xinmei Wu, Jiale Yu, JinJing Li, Xiaoyuan Huang, Chunfang Zhu, and Hongshan Ge. "Yap regulates mitochondrial structural remodeling during myoblast differentiation." American Journal of Physiology-Cell Physiology 315, no. 4 (October 1, 2018): C474—C484. http://dx.doi.org/10.1152/ajpcell.00112.2018.
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Yes-associated protein (Yap) is a core transcriptional coactivator in the downstream Hippo pathway that regulates cell proliferation and tissue growth. However, its role in the regulation of myoblast differentiation remains unclear. Regulation of mitochondrial networks by dynamin-related protein 1 (Drp1) and mitofusion 2 (Mfn2) is crucial for the activation of myoblast differentiation. In the present study, we investigated the interplay between the Hippo/Yap pathway and protein contents of Mfn2 and Drp1 during myoblast differentiation. The Hippo/Yap pathway was inactivated at the early stage of myoblast differentiation due to the decreased ratio of phosphorylated mammalian sterile 20 kinases 1/2 (p-Mst1/2) to Mst1/2, phosphorylated large tumor suppressor 1 (p-Lats1) to Lats1, and phosphorylated Yap (serine 112, p-Yap S112) to Yap, which resulted in the translocation of Yap from cytoplasm to nucleus, increased protein content of Drp1, and mitochondrial fission events. Downregulation of Yap inhibited myoblast differentiation and decreased the content of Drp1, which resulted in elongated mitochondria, fused mitochondrial networks, and collapsed mitochondrial membrane potential. Together, our data indicate that inactivation of the Hippo/Yap pathway could induce mitochondrial fission by promoting Drp1 content at the early stage of myoblast differentiation.
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Jagannathan, Radhika, Gregory V. Schimizzi, Kun Zhang, Andrew J. Loza, Norikazu Yabuta, Hitoshi Nojima, and Gregory D. Longmore. "AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol." Molecular and Cellular Biology 36, no. 20 (July 25, 2016): 2526–42. http://dx.doi.org/10.1128/mcb.00136-16.
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The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling duringDrosophilawing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.
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Höffken, Verena, Anke Hermann, Hermann Pavenstädt, and Joachim Kremerskothen. "WWC Proteins: Important Regulators of Hippo Signaling in Cancer." Cancers 13, no. 2 (January 15, 2021): 306. http://dx.doi.org/10.3390/cancers13020306.
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The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is crucial for organ size control and the prevention of tumor formation. The transcriptional activity of YAP is controlled by a growing number of upstream regulators including the family of WWC proteins. WWC1, WWC2 and WWC3 represent cytosolic scaffolding proteins involved in intracellular transport processes and different signal transduction pathways. Earlier in vitro experiments demonstrated that WWC proteins positively regulate the Hippo pathway via the activation of large tumor suppressor kinases 1/2 (LATS1/2) kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP. Later, reduced WWC expression and subsequent high YAP activity were shown to correlate with the progression of human cancer in different organs. Although the function of WWC proteins as upstream regulators of Hippo signaling was confirmed in various studies, their important role as tumor modulators is often overlooked. This review has been designed to provide an update on the published data linking WWC1, WWC2 and WWC3 to cancer, with a focus on Hippo pathway-dependent mechanisms.
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Thaventhiran, James, Anja Hoffmann, and Douglas Fearon. "CTLA-4 activates the hippo pathway to regulate terminal differentiation of the CD8+ T cell. (46.17)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 46.17. http://dx.doi.org/10.4049/jimmunol.186.supp.46.17.
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Abstract Replicating, antigen-specific CD8+ T cells must not commit to terminal differentiation until there has been sufficient clonal expansion. The Hippo pathway of organ size control mediates this requirement by linking expression of the differentiation-inducing transcription factor, Blimp-1, to contact between replicating cells, which would be dependent on their frequency. TCR and IL-2R stimulation assemble the Hippo pathway in the CD8+ T cell by inducing expression of WW45, Mob1, Lats1, and YAP, the transcriptional co-activator that mediates organ growth. Contact between activated CD8+ T cells triggers the Hippo pathway, causing serine phosphorylation and degradation of YAP. This is suppressed by addition of naïve CD8+ T cells, indicating that the ligand-receptor pair triggering the Hippo pathway is expressed only by activated cells. The ligand was identified by suppressing YAP degradation with blocking CD80/86 antibody, and the receptor was defined by inducing YAP degradation by crosslinking CTLA-4. That YAP regulates differentiation was shown by ectopically expressing a non-phosphorylatable, stable form of YAP in activated CD8+ T cells, which suppressed Blimp-1 expression in vitro, and the differentiation/senescence marker, KLRG1, in vivo. This role for CTLA-4 was confirmed by the presence of YAP in T cells from CTLA-4-/-, but not CTLA-4+/-, mice. Therefore, in a process that resembles quorum sensing, the Hippo pathway regulates terminal differentiation of the CD8+ T cell.
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Casati, G., L. Giunti, A. Iorio, A. Marturano, and I. Sardi. "P04.20 The role of YAP in Glioblastoma cell lines." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii22—ii23. http://dx.doi.org/10.1093/neuonc/noab180.074.
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Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.
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Werneburg, Nathan, Gregory J. Gores, and Rory L. Smoot. "The Hippo Pathway and YAP Signaling: Emerging Concepts in Regulation, Signaling, and Experimental Targeting Strategies With Implications for Hepatobiliary Malignancies." Gene Expression 20, no. 1 (June 12, 2020): 67–74. http://dx.doi.org/10.3727/105221619x15617324583639.
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The Hippo pathway and its effector protein YAP (a transcriptional coactivator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila, the understanding of the mammalian YAP signaling and its regulation continues to expand. In its “on” function, the canonical regulatory Hippo pathway, a well-described serine/threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm. In contrast, when the Hippo pathway is “off,” YAP translocates to the nucleus and drives cotranscriptional activity. Given the role of Hippo/YAP signaling in hepatic malignancies, investigators have sought to target these molecules; however, standard approaches have not been successful based on the pathways’ negative regulatory role. More recently, additional regulatory mechanisms, such as tyrosine phosphorylation, of YAP have been described. These represent positive regulatory events that may be targetable. Additionally, several groups have identified potentiating feed-forward signaling for YAP in multiple contexts, suggesting other experimental therapeutic approaches to interrupt these signaling loops. Herein we explore the current data supporting alternative YAP regulatory pathways, review the described feed-forward signaling cascades that are YAP dependent, and explore targeting strategies that have been employed in preclinical models of hepatic malignancies.
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Wong, Jenny S., Kristin Meliambro, Justina Ray, and Kirk N. Campbell. "Hippo signaling in the kidney: the good and the bad." American Journal of Physiology-Renal Physiology 311, no. 2 (August 1, 2016): F241—F248. http://dx.doi.org/10.1152/ajprenal.00500.2015.
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The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.
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Zhou, Wenyi, and Mingyi Zhao. "How Hippo Signaling Pathway Modulates Cardiovascular Development and Diseases." Journal of Immunology Research 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/3696914.
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Cardiovascular disease remains the leading cause of death around the globe. Cardiac deterioration is associated with irreversible cardiomyocyte loss. Understanding how the cardiovascular system develops and the pathological processes of cardiac disease will contribute to finding novel and preventive therapeutic methods. The canonical Hippo tumor suppressor pathway in mammalian cells is primarily composed of the MST1/2-SAV1-LATS1/2-MOB1-YAP/TAZ cascade. Continuing research on this pathway has identified other factors like RASSF1A, Nf2, MAP4Ks, and NDR1/2, further enriching our knowledge of the Hippo-YAP pathway. YAP, the core effecter of the Hippo pathway, may accumulate in the nucleus and initiate transcriptional activity if the pathway is inhibited. The role of Hippo signaling has been widely investigated in organ development and cancers. A heart of normal size and function which is critical for survival could not be generated without the proper regulation of the Hippo tumor suppressor pathway. Recent research has demonstrated a novel role of Hippo signaling in cardiovascular disease in the context of development, hypertrophy, angiogenesis, regeneration, apoptosis, and autophagy. In this review, we summarize the current knowledge of how Hippo signaling modulates pathological processes in cardiovascular disease and discuss potential molecular therapeutic targets.
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Kim, Yong Joon, Eunji Jung, Eunbie Shin, Sin-Hyoung Hong, Hui Su Jeong, Gayeong Hur, Hye Yun Jeong, et al. "Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation." Proceedings of the National Academy of Sciences 117, no. 33 (August 3, 2020): 19994–20003. http://dx.doi.org/10.1073/pnas.1915387117.
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The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.
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Song, Yong, Jing Fu, Min Zhou, Li Xiao, Xue Feng, Hengxi Chen, and Wei Huang. "Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis." Journal of Clinical Endocrinology & Metabolism 101, no. 4 (April 1, 2016): 1552–61. http://dx.doi.org/10.1210/jc.2016-1120.
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Abstract Context: The imbalance in cell proliferation and apoptosis is considered an important role in the pathogenesis of endometriosis, but the exact mechanisms remains unclear. A newly established signaling pathway–Hippo/Yes-associated protein (YAP) pathway plays a critical role in the proliferation and apoptosis processes. However, studies focusing on Hippo/YAP pathway and endometriosis are lacking. Objective: The objective was to explore the function of the Hippo/YAP pathway in endometriosis. Setting and Design: The expression of YAP was first investigated in endometrium of women with or without endometriosis. The role of YAP in cell proliferation and apoptosis is identified by transfection of endometrial stromal cells (ESCs) in vitro, subsequent Verteporfin treatments in eutopic ESCs in vitro, and endometriosis animal model of nude mice in vivo. Results: Our results revealed that increased expression of YAP and decreased expression of p-YAP in ectopic and eutopic endometrium compared with normal endometrium. YAP knockdown in eutopic ESCs decreased cell proliferation and enhanced cell apoptosis companied with decreased expression of TEAD1, CTGF, and B-cell lymphoma/leukemia (BCL)-2; whereas overexpression of YAP resulted in increased proliferation and decreased apoptosis of normal ESCs with increased expression of TEAD1, CTGF, and BCL-2. By chromatin immunoprecipitation qPCR CTGF and BCL-2 were identified as directly downstream target genes of YAP-TEAD1 active complex. Eutopic ESCs treated with Verteporfin revealed decreased proliferation and enhanced apoptosis whereas in endometriosis animal models of nude mice treated with Verteporfin, the size of endometriotic lesions was significantly reduced. Conclusions: Our study suggests that the Hippo/YAP-signaling pathway plays a critical role in the pathogenesis of endometriosis and should present a novel therapeutic method against endometriosis.
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Koinis, Filippos, Evangelia Chantzara, Michael Samarinas, Anastasia Xagara, Zisis Kratiras, Vasiliki Leontopoulou, and Athanasios Kotsakis. "Emerging Role of YAP and the Hippo Pathway in Prostate Cancer." Biomedicines 10, no. 11 (November 7, 2022): 2834. http://dx.doi.org/10.3390/biomedicines10112834.
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The Hippo pathway regulates and contributes to several hallmarks of prostate cancer (PCa). Although the elucidation of YAP function in PCa is in its infancy, emerging studies have shed light on the role of aberrant Hippo pathway signaling in PCa development and progression. YAP overexpression and nuclear localization has been linked to poor prognosis and resistance to treatment, highlighting a therapeutic potential that may suggest innovative strategies to treat cancer. This review aimed to summarize available data on the biological function of the dysregulated Hippo pathway in PCa and identify knowledge gaps that need to be addressed for optimizing the development of YAP-targeted treatment strategies in patients likely to benefit.
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Ahmad, Usama Sharif, Jutamas Uttagomol, and Hong Wan. "The Regulation of the Hippo Pathway by Intercellular Junction Proteins." Life 12, no. 11 (November 5, 2022): 1792. http://dx.doi.org/10.3390/life12111792.
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The Hippo pathway is an evolutionarily conserved pathway that serves to promote cell death and differentiation while inhibiting cellular proliferation across species. The downstream effectors of this pathway, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are considered vital in promoting the output of the Hippo pathway, with activation of upstream kinases negatively regulating YAP/TAZ activity. The upstream regulation of the Hippo pathway is not entirely understood on a molecular level. However, several studies have shown that numerous cellular and non-cellular mechanisms such as cell polarity, contact inhibition, soluble factors, mechanical forces, and metabolism can convey external stimuli to the intracellular kinase cascade, promoting the activation of key components of the Hippo pathway and therefore regulating the subcellular localisation and protein activity of YAP/TAZ. This review will summarise what we have learnt about the role of intercellular junction-associated proteins in the activation of this pathway, including adherens junctions and tight junctions, and in particular our latest findings about the desmosomal components, including desmoglein-3 (DSG3), in the regulation of YAP signalling, phosphorylation, and subcellular translocation.
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Liu, Yuchen, Xiaohui Wang, and Yingzi Yang. "Hepatic Hippo signaling inhibits development of hepatocellular carcinoma." Clinical and Molecular Hepatology 26, no. 4 (October 1, 2020): 742–50. http://dx.doi.org/10.3350/cmh.2020.0178.
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Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.
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Gujral, Taranjit S., and Marc W. Kirschner. "Hippo pathway mediates resistance to cytotoxic drugs." Proceedings of the National Academy of Sciences 114, no. 18 (April 17, 2017): E3729—E3738. http://dx.doi.org/10.1073/pnas.1703096114.
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Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models. Nuclear YAP enhances gemcitabine effectiveness by down-regulating multidrug transporters as well by converting gemcitabine to a less active form, both leading to its increased intracellular availability. Cancer cell lines carrying genetic aberrations that impair the Hippo signaling pathway showed heightened sensitivity to gemcitabine. These findings suggest that “switching off” of the Hippo–YAP pathway could help to prevent or reverse resistance to some cancer therapies.
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Fu, David, Xiangmin Lv, Guohua Hua, Chunbo He, Jixin Dong, Subodh M. Lele, David Wan-Cheng Li, Qiongli Zhai, John S. Davis, and Cheng Wang. "YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors." Endocrine-Related Cancer 21, no. 2 (January 3, 2014): 297–310. http://dx.doi.org/10.1530/erc-13-0339.
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The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes-associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of the ovary, excess production of estrogen, a high frequency of recurrence, and the potential for malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild type YAP or a constitutively active YAP (YAP1) mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in the regulation of GCT cell proliferation, migration, and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT.
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Kim, Nam-Gyun, and Barry M. Gumbiner. "Adhesion to fibronectin regulates Hippo signaling via the FAK–Src–PI3K pathway." Journal of Cell Biology 210, no. 3 (July 27, 2015): 503–15. http://dx.doi.org/10.1083/jcb.201501025.
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The Hippo pathway is involved in the regulation of contact inhibition of proliferation and responses to various physical and chemical stimuli. Recently, several upstream negative regulators of Hippo signaling, including epidermal growth factor receptor ligands and lysophosphatidic acid, have been identified. We show that fibronectin adhesion stimulation of focal adhesion kinase (FAK)-Src signaling is another upstream negative regulator of the Hippo pathway. Inhibition of FAK or Src in MCF-10A cells plated at low cell density prevented the activation of Yes-associated protein (YAP) in a large tumor suppressor homologue (Lats)–dependent manner. Attachment of serum-starved MCF-10A cells to fibronectin, but not poly-d-lysine or laminin, induced YAP nuclear accumulation via the FAK–Src–phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) signaling pathway. Attenuation of FAK, Src, PI3K, or PDK1 activity blocked YAP nuclear accumulation stimulated by adhesion to fibronectin. This negative regulation of the Hippo pathway by fibronectin adhesion signaling can, at least in part, explain the effects of cell spreading on YAP nuclear localization and represents a Lats-dependent component of the response to cell adhesion.
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Huang, Yunying, Usama Sharif Ahmad, Ambreen Rehman, Jutamas Uttagomol, and Hong Wan. "YAP Inhibition by Verteporfin Causes Downregulation of Desmosomal Genes and Proteins Leading to the Disintegration of Intercellular Junctions." Life 12, no. 6 (May 26, 2022): 792. http://dx.doi.org/10.3390/life12060792.
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The Hippo-YAP pathway serves as a central signalling hub in epithelial tissue generation and homeostasis. Yes-associated protein (YAP) is an essential downstream transcription cofactor of this pathway, with its activity being negatively regulated by Hippo kinase-mediated phosphorylation, leading to its cytoplasmic translocation or degradation. Our recent study showed phospho-YAP complexes with Desmoglein-3 (Dsg3), the desmosomal cadherin known to be required for junction assembly and cell–cell adhesion. In this study, we show that YAP inhibition by Verteporfin (VP) caused a significant downregulation of desmosomal genes and a remarkable reduction in desmosomal proteins, including the Dsg3/phospho-YAP complex, resulting in attenuation of cell cohesion. We also found the desmosomal genes, along with E-cadherin, were the YAP-TEAD transcriptional targets and Dsg3 regulated key Hippo components, including WWTR1/TAZ, LATS2 and the key desmosomal molecules. Furthermore, Dsg3 and phospho-YAP exhibited coordinated regulation in response to varied cell densities and culture durations. Overexpression of Dsg3 could compensate for VP mediated loss of adhesion components and proper architecture of cell junctions. Thus, our findings suggest that Dsg3 plays a crucial role in the Hippo network and regulates junction configuration via complexing with phospho-YAP.
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Luo, Jiaqian, and Fa-Xing Yu. "GPCR-Hippo Signaling in Cancer." Cells 8, no. 5 (May 8, 2019): 426. http://dx.doi.org/10.3390/cells8050426.
Full textAbstract:
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.
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Chuang, Linda, and Yoshiaki Ito. "The Multiple Interactions of RUNX with the Hippo–YAP Pathway." Cells 10, no. 11 (October 28, 2021): 2925. http://dx.doi.org/10.3390/cells10112925.
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The Hippo–YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog TAZ by modulating cell proliferation and promoting differentiation to maintain tissue homeostasis and proper organ size. Similarly, master regulators of development RUNX transcription factors have been shown to play critical roles in proliferation, differentiation, apoptosis and cell fate determination. In this review, we discuss the multiple interactions of RUNX with the Hippo–YAP pathway, their shared collaborators in Wnt, TGFβ, MYC and RB pathways, and their overlapping functions in development and tumorigenesis.
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Mougel, G., G. Mondielli, R. Appay, A. Querdray, C. Roche, A. Jijon, I. Konstantinova, A. Soude, T. Graillon, and A. Barlier. "P18.07.A Hippo signaling pathway is strongly involved in meningioma tumorigenesis." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii95. http://dx.doi.org/10.1093/neuonc/noac174.334.
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Abstract Background Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In mammals, Hippo signaling pathway is responsible for the growth of organs by regulating cell proliferation and apoptosis. The tumor suppressor NF2 protein belongs to the core of the Hippo pathway and a defect of its gene is present in 50% of meningiomas. Absence of NF2 keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the nucleus and the formation of a complex with TEADs. This complex then promotes the transcription of anti-apoptotic and proliferative genes such as CTGF, CYR61 and AXL. Here we present experimental results on human meningioma fragments and primary cell cultures supporting that Hippo pathway plays a critical role in meningioma tumorigenesis. Material and Methods The role of the Hippo pathway was studied on 57 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and TEADs. Results Fifty-seven meningiomas were randomly selected including 27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2 gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented a significant increase of expression levels of Hippo pathway target transcripts CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p<0.0001, p=0.0072 and p=0.0191, respectively). This increase was not correlated with the grade, the sex or with the cerebral localization of the meningiomas. On the other side, IHC analysis suggested this increase was correlated with the nuclear localization of YAP. Disturbing the YAP/TAZ-TEADs complex using siRNA on 10 meningiomas (5 NF2 wild-type and 5 NF2 def) induced a significant decrease on cell proliferation but not on cell viability. This decrease was more important when TAZ was turned off in comparison to turning off of YAP. Conclusion Our experimental results strongly support the importance of the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a new target in meningioma therapy. A.Barlier reports receiving research grants from Inventiva Pharma. No potential conflicts of interest were disclosed by the other authors.
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Bednarski, Igor Aleksander, Magdalena Ciążyńska, Karolina Wódz, Izabela Dróżdż, Małgorzata Skibińska, Joanna Narbutt, and Aleksandra Lesiak. "Hippo Signaling Pathway as a New Potential Target in Non-Melanoma Skin Cancers: A Narrative Review." Life 11, no. 7 (July 12, 2021): 680. http://dx.doi.org/10.3390/life11070680.
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Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most frequently diagnosed cancers in humans, however, their exact pathogenesis is not fully understood. In recent years, it has been hypothesized that the recently discovered Hippo pathway could play a detrimental role in cutaneous carcinogenesis, but no direct connections have been made. The Hippo pathway and its effector, YAP, are responsible for tissue growth by accelerating cell proliferation, however, YAP upregulation and overexpression have also been reported in numerous types of tumors. There is also evidence that disrupted YAP/Hippo signaling is responsible for cancer growth, invasion, and metastasis. In this short review, we will explore whether the Hippo pathway is an important regulator of skin carcinogenesis and if it could be a promising target for future therapies.
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Nouri, Kazem, Taha Azad, Min Ling, Helena J. Janse van Rensburg, Alexander Pipchuk, He Shen, Yawei Hao, Jianmin Zhang, and Xiaolong Yang. "Identification of Celastrol as a Novel YAP-TEAD Inhibitor for Cancer Therapy by High Throughput Screening with Ultrasensitive YAP/TAZ–TEAD Biosensors." Cancers 11, no. 10 (October 19, 2019): 1596. http://dx.doi.org/10.3390/cancers11101596.
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The Hippo pathway has emerged as a key signaling pathway that regulates a broad range of biological functions, and dysregulation of the Hippo pathway is a feature of a variety of cancers. Given this, some have suggested that disrupting the interaction of the Hippo core component YAP and its paralog TAZ with transcriptional factor TEAD may be an effective strategy for cancer therapy. However, there are currently no clinically available drugs targeting the YAP/TAZ–TEAD interaction for cancer treatment. To facilitate screens for small molecule compounds that disrupt the YAP–TEAD interaction, we have developed the first ultra-bright NanoLuc biosensor to quantify YAP/TAZ–TEAD protein–protein interaction (PPI) both in living cells and also in vitro using biosensor fusion proteins purified from bacteria. Using this biosensor, we have performed an in vitro high throughput screen (HTS) of small molecule compounds and have identified and validated the drug Celastrol as a novel inhibitor of YAP/TAZ–TEAD interaction. We have also demonstrated that Celastrol can inhibit cancer cell proliferation, transformation, and cell migration. In this study, we describe a new inhibitor of the YAP/TAZ–TEAD interaction warranting further investigation and offer a novel biosensor tool for the discovery of other new Hippo-targeting drugs in future work.
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Ji, Xinyan, Lihua Song, Li Sheng, Anhui Gao, Yang Zhao, Shixun Han, Yuchao Zhang, et al. "Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation." Cancers 10, no. 11 (November 16, 2018): 449. http://dx.doi.org/10.3390/cancers10110449.
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The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.
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Feng, Chen, Bruce Song, and Xiyang Peng. "Research Progress of Hippo-Yap/Taz Signaling in Skeletal Muscle Hypertrophy." Current Research in Medical Sciences 2, no. 1 (March 2023): 37–47. http://dx.doi.org/10.56397/crms.2023.03.06.
Full textAbstract:
The Hippo pathway is an important pathway to control cell proliferation and organ size. By sensing extracellular matrix stiffness and intercellular mechanical force and converting them into molecular signal transduction, through a series of cascade amplification effects of kinases, the final the phosphorylation of YAP/TAZ, the main downstream target of the Hippo pathway, plays a series of regulatory roles. Although many studies have shown that Hippo signaling changes during skeletal muscle hypertrophy, the complex mechanism of Hippo signaling in skeletal muscle hypertrophy remains to be further studied. In this review, we summarize the relationship between Hippo-YAP/TAZ signaling and skeletal muscle hypertrophy and sort out the contribution of the main factors in the process of skeletal muscle hypertrophy.
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Habbig, Sandra, Malte P. Bartram, Roman U. Müller, Ricarda Schwarz, Nikolaos Andriopoulos, Shuhua Chen, Josef G. Sägmüller, et al. "NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway." Journal of Cell Biology 193, no. 4 (May 9, 2011): 633–42. http://dx.doi.org/10.1083/jcb.201009069.
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The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.
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Shin, Eunbie, and Joon Kim. "The potential role of YAP in head and neck squamous cell carcinoma." Experimental & Molecular Medicine 52, no. 8 (August 2020): 1264–74. http://dx.doi.org/10.1038/s12276-020-00492-9.
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Abstract The transcriptional cofactor YAP and its inhibitory regulators, Hippo kinases and adapter proteins, constitute an evolutionarily conserved signaling pathway that controls organ size and cell fate. The activity of the Hippo-YAP pathway is determined by a variety of intracellular and intercellular cues, such as cell polarity, junctions, density, mechanical stress, energy status, and growth factor signaling. Recent studies have demonstrated that YAP can induce the expression of a set of genes that allow cancer cells to gain a survival advantage and aggressive behavior. Comprehensive genomic studies have revealed frequent focal amplifications of the YAP locus in human carcinomas, including head and neck squamous cell carcinoma (HNSCC). Moreover, FAT1, which encodes an upstream component of Hippo signaling, is one of the most commonly altered genes in HNSCC. In this review, we discuss the causes and functional consequences of YAP dysregulation in HNSCC. We also address interactions between YAP and other oncogenic drivers of HNSCC.
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Ma, Xianjue, Hongxiang Wang, Jiansong Ji, Wenyan Xu, Yihao Sun, Wenzhe Li, Xiaoping Zhang, Juxiang Chen, and Lei Xue. "Hippo signaling promotes JNK-dependent cell migration." Proceedings of the National Academy of Sciences 114, no. 8 (February 7, 2017): 1934–39. http://dx.doi.org/10.1073/pnas.1621359114.
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Overwhelming studies show that dysregulation of the Hippo pathway is positively correlated with cell proliferation, growth, and tumorigenesis. Paradoxically, the detailed molecular roles of the Hippo pathway in cell invasion remain debatable. Using aDrosophilainvasion model in wing epithelium, we show herein that activated Hippo signaling promotes cell invasion and epithelial-mesenchymal transition through JNK, as inhibition of JNK signaling dramatically blocked Hippo pathway activation-induced matrix metalloproteinase 1 expression and cell invasion. Furthermore, we identifybantam-Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Finally, we confirm that YAP (Yes-associated protein) expression negatively regulates TIA1 (Rox8 ortholog) expression and cell invasion in human cancer cells. Together, these findings provide molecular insights into Hippo pathway-mediated cell invasion and also raise a noteworthy concern in therapeutic interventions of Hippo-related cancers, as simply inhibiting Yorkie or YAP activity might paradoxically accelerate cell invasion and metastasis.
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Avalos-de León, Cindy G., Mónica B. Jiménez-Castro, María Eugenia Cornide-Petronio, José Gulfo, Floriana Rotondo, Jordi Gracia-Sancho, Araní Casillas-Ramírez, and Carmen Peralta. "The Effect of Fibroblast Growth Factor 15 Signaling in Non-Steatotic and Steatotic Liver Transplantation from Cardiocirculatory Death." Cells 8, no. 12 (December 14, 2019): 1640. http://dx.doi.org/10.3390/cells8121640.
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We elucidate the relevance of fibroblast growth factor 15 (FGF15) in liver transplantation (LT) using rats with both steatotic and non-steatotic organs from donors after cardiocirculatory death (DCD). Compared to LT from non-DCDs, the induction of cardiocirculatory death (CD) increases hepatic damage, proliferation, and intestinal and circulatory FGF15. This is associated with high levels of FGF15, bilirubin and bile acids (BAs), and overexpression of the enzyme involved in the alternative BA synthesis pathway, CYP27A1, in non-steatotic livers. Furthermore, CD activates the proliferative pathway, Hippo/YAP, in these types of liver. Blocking FGF15 action in LT from DCDs does not affect CYP27A1 but causes an overexpression of CYP7A, an enzyme from the classic BA synthesis pathway, and this is related to further accumulation of BAs and exacerbated damage. FGF15 inhibition also impairs proliferation without changing Hippo/YAP. In spite of worse damage, steatosis prevents a proliferative response in livers from DCDs. In steatotic grafts, CD does not modify CYP7A1, CYP27A1, BA, or the Hippo/YAP pathway, and FGF15 is not involved in damage or proliferation. Thus, endogenous FGF15 protects against BA accumulation and damage and promotes regeneration independently of the Hippo/YAP pathway, in non-steatotic LT from DCDs. Herein we show a minor role of FGF15 in steatotic LT from DCDs.
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Xiong, Wenjie, Shuhua Yi, Yuting Yan, Zengjun Li, Wei Liu, Rui Lv, Zhen Yu, Dehui Zou, and Lugui Qiu. "Inhibiting the Hippo Signaling Pathway Key Molecule YAP Suppresses Mantle Cell Lymphoma Proliferation By Regulating Multiple Pathogenrelated Signaling Pathways." Blood 134, Supplement_1 (November 13, 2019): 2566. http://dx.doi.org/10.1182/blood-2019-129860.
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Object: Mantle cell lymphoma (MCL) is a rare hematologic malignancy with heterogeneous course and always resistant to chemotherapy at advance or relapsed stage. Hippo signaling pathway is one of the most popular pathways in solid tumors. The major role of this pathway is regulating cell proliferation, migration, and maintaining the stemness of cells. However, the relationship between this pathway and MCL had been rarely studied. The purpose of this study is to investigate the relationship between MCL and YAP, the key molecule Hippo signaling pathway, to further clarify the mechanism of MCL resistance and to find new therapeutic targets. Methods: In this study, expression of YAP in B cell non-hodgkin's lymphoma (B-NHL) and mantle cell lymphoma detected by real-time PCR, Western blot analysis, immunofluorescence. Knockdown of YAP by sh-RNA or inhibit the function of YAP using verteporfin (VP). Next, the effects of YAP knockdown and YAP inhibitor on MCL cells were evaluated by fluorescence detection, real-time PCR and Western blot. Cell count, CCK8, Soft Agar Assay and in vitro functional assays were performed to elucidate the function of YAP-mediated cell proliferation, the effect on signaling pathway and the relationship with chemoresistance in MCL. Results: We detected the expression of YAP in 40 B-NHL patients and 10 healthy donor and found that YAP were overexpressed in relapsed and newly diagnosis patients and it was extremely higher in relapsed patients. Moreover, YAP is extremely high express on MCL. Knockdown YAP by shRNA or YAP inhibitor verteporfin (VP) could not only inhibit the proliferation, induce the apoptosis of MCL cell lines, but also lead to cells stopping in G1 phase. In addition, knockdown YAP could sensitize Z138 cells to the cytotoxics of BTK inhibitors ibrutinib and SYK inhibitor R788.Combined VP and ibrutinib or R788 had obvious synergy. Most importantly, knockdown YAP could obviously reduce the expression of protein involved in G1 phase, inhibit the BCR signaling pathway and PI3K AKT signaling pathway, and promote cell apoptosis and DNA damage signaling pathways. Through regulating multiple signaling pathways, YAP played an important role in cell proliferation and drug resistance in B-NHL. Conclusion: It was the first time to demonstrate that Hippo signaling pathways may associate with the pathogenesis and drug resistance of MCL. Targeting the key molecular of Hippo signaling pathways may be potential therapeutic targets of MCL patients especially the relapse and refractory patients. Disclosures No relevant conflicts of interest to declare.
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Park, Jiwon, and Carsten Gram Hansen. "Cellular feedback dynamics and multilevel regulation driven by the hippo pathway." Biochemical Society Transactions 49, no. 4 (August 10, 2021): 1515–27. http://dx.doi.org/10.1042/bst20200253.
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The Hippo pathway is a dynamic cellular signalling nexus that regulates differentiation and controls cell proliferation and death. If the Hippo pathway is not precisely regulated, the functionality of the upstream kinase module is impaired, which increases nuclear localisation and activity of the central effectors, the transcriptional co-regulators YAP and TAZ. Pathological YAP and TAZ hyperactivity consequently cause cancer, fibrosis and developmental defects. The Hippo pathway controls an array of fundamental cellular processes, including adhesion, migration, mitosis, polarity and secretion of a range of biologically active components. Recent studies highlight that spatio-temporal regulation of Hippo pathway components are central to precisely controlling its context-dependent dynamic activity. Several levels of feedback are integrated into the Hippo pathway, which is further synergized with interactors outside of the pathway that directly regulate specific Hippo pathway components. Likewise, Hippo core kinases also ‘moonlight’ by phosphorylating multiple substrates beyond the Hippo pathway and thereby integrates further flexibility and robustness in the cellular decision-making process. This topic is still in its infancy but promises to reveal new fundamental insights into the cellular regulation of this therapeutically important pathway. We here highlight recent advances emphasising feedback dynamics and multilevel regulation of the Hippo pathway with a focus on mitosis and cell migration, as well as discuss potential productive future research avenues that might reveal novel insights into the overall dynamics of the pathway.
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Bottini, Angel, Dennis J. Wu, Rizi Ai, Michelle Le Roux, Beatrix Bartok, Michele Bombardieri, Karen M. Doody, et al. "PTPN14 phosphatase and YAP promote TGFβ signalling in rheumatoid synoviocytes." Annals of the Rheumatic Diseases 78, no. 5 (February 26, 2019): 600–609. http://dx.doi.org/10.1136/annrheumdis-2018-213799.
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ObjectiveWe aimed to understand the role of the tyrosine phosphatase PTPN14—which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol—in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).MethodsGene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis.ResultsRA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFβ-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP—but not of a non-YAP-interacting PTPN14 mutant—enhanced SMAD reporter activity. YAP promoted TGFβ-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity.ConclusionIn RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.
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Jie, Lu, Wang Fan, Dai Weiqi, Zhou Yingqun, Xu Ling, Shen Miao, Cheng Ping, and Guo Chuanyong. "The Hippo-Yes Association Protein Pathway in Liver Cancer." Gastroenterology Research and Practice 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/187070.
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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer mortality. Despite continuing development of new therapies, prognosis for patients with HCC remains extremely poor. In recent years, control of organ size becomes a hot topic in HCC development. The Hippo signaling pathway has been delineated and shown to be critical in controlling organ size in both Drosophila and mammals. The Hippo kinase cascade, a singling pathway that antagonizes the transcriptional coactivator Yes-associated protein (YAP), plays an important role in animal organ size control by regulating cell proliferation and apoptosis rates. During HCC development, this pathway is likely inactivated in tumor initiated cells that escape suppressive constrain exerted by the surrounding normal tissue, thus allowing clonal expansion and tumor development. We have reviewed evolutionary changes in YAP as well as other components of the Hippo pathway and described the relationships between YAP genes and HCC. We also discuss regulation of transcription factors that are up- and downstream of YAP in liver cancer development.
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Bae, June Sung, Sun Mi Kim, Yoon Jeon, Juyeon Sim, Ji Yun Jang, Jaehyung Son, Woosol Hong, Mi Kyung Park, and Ho Lee. "Loss of Mob1a/b impairs the differentiation of mouse embryonic stem cells into the three germ layer lineages." Experimental & Molecular Medicine 51, no. 11 (November 2019): 1–12. http://dx.doi.org/10.1038/s12276-019-0342-z.
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AbstractThe Hippo pathway plays a crucial role in cell proliferation and apoptosis and can regulate stem cell maintenance and embryonic development. MOB kinase activators 1A and 1B (Mob1a/b) are key components of the Hippo pathway, whose homozygous deletion in mice causes early embryonic lethality at the preimplantation stage. To investigate the role of Mob1a/b in stem cell maintenance and differentiation, an embryonic stem cell (ESC) clone in which Mob1a/b could be conditionally depleted was generated and characterized. Although Mob1a/b depletion did not affect the stemness or proliferation of mouse ESCs, this depletion caused defects in differentiation into the three germ layers. Yap knockdown rescued the in vitro and in vivo defects in differentiation caused by Mob1a/b depletion, suggesting that differentiation defects caused by Mob1a/b depletion were Yap-dependent. In teratoma experiments, Yap knockdown in Mob1a/b-depleted ESCs partially restored defects in differentiation, indicating that hyperactivation of Taz, another effector of the Hippo pathway, inhibited differentiation into the three germ layers. Taken together, these results suggest that Mob1a/b or Hippo signaling plays a critical role in the differentiation of mouse ESCs into the three germ layers, which is dependent on Yap. These close relationship of the Hippo pathway with the differentiation of stem cells supports its potential as a therapeutic target in regenerative medicine.
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Tran, Thi Hai Yen, Dae-Wook Yang, Minchul Kim, Da-Hye Lee, Marta Gai, Ferdinando Di Cunto, Kwang-Wook Choi, and Dae-Sik Lim. "Citron kinase interacts with LATS2 and inhibits its activity by occluding its hydrophobic phosphorylation motif." Journal of Molecular Cell Biology 11, no. 11 (March 13, 2019): 1006–17. http://dx.doi.org/10.1093/jmcb/mjz013.
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Abstract The inhibitory effect of large tumor suppressor kinase (LATS1/2) on the activity of the oncoprotein yes-associated protein (YAP) is crucial to maintain tissue homeostasis. Proteomic studies have identified several new regulators of this process. Recently, citron kinase (CIT) was listed as a potential binding candidate of Hippo-related components, suggesting a new connection between CIT and the Hippo pathway. Aside from CIT’s role in cytokinesis, the molecular crosstalk between CIT and the Hippo pathway is largely unknown. Here, we demonstrate a role for CIT as a scaffold protein linking LATS2 and YAP. More importantly, CIT interacts with LATS2 to directly suppress LATS2 phosphorylation at the hydrophobic motif—targeted by MST1, leading to LATS2 inactivation and YAP activation. By studying their genetic interactions, we found that Sticky, the CIT homolog in Drosophila melanogaster, functions with Warts to control Drosophila eye development. Together, our study confirms citron kinase as a novel regulator of the Hippo pathway.
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Hori, Naoto, Kazuyuki Okada, Yuki Takakura, Hiroyuki Takano, Naoto Yamaguchi, and Noritaka Yamaguchi. "Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway." Journal of Biological Chemistry 295, no. 26 (May 8, 2020): 8798–807. http://dx.doi.org/10.1074/jbc.ra120.012781.
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Vestigial-like 3 (VGLL3) is a member of the VGLL family, whose members serve as cofactors for TEA domain–containing transcription factors (TEADs). TEADs promote tissue and tumor development together with the cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although VGLL3 is involved in tumor cell proliferation, its relationship with TEADs and YAP/TAZ remains largely unknown. To close this research gap, here we established tumor cells stably expressing VGLL3 and found that they exhibit enhanced proliferation. Notably, YAP and TAZ were inactivated in the VGLL3-expressing cells, coinciding with activation of the Hippo pathway, which suppresses YAP/TAZ activities. VGLL3 in combination with TEADs promoted expression of the Hippo pathway components large tumor suppressor kinase (LATS2) and angiomotin-like 2 (AMOTL2). VGLL3 was highly expressed in malignant breast tumor cells and osteosarcoma cells, and VGLL3 knockdown increased nuclear localization of YAP and TAZ. Knockdown of LATS2 or AMOTL2, as well as VGLL3 knockdown, repressed proliferation of breast tumor cells. Together, these results suggest that VGLL3 together with TEADs promotes cell proliferation by activating the Hippo pathway through LATS2 and AMOTL2, leading to YAP/TAZ inactivation.
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Santos-de-Frutos, Karla, Carmen Segrelles, and Corina Lorz. "Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck." Journal of Clinical Medicine 8, no. 12 (December 3, 2019): 2131. http://dx.doi.org/10.3390/jcm8122131.
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Head and neck cancer affects the upper aerodigestive tract and is the sixth leading cancer worldwide by incidence and the seventh by cause of death. Despite significant advances in surgery and chemotherapy, molecularly targeted therapeutic options for this type of cancer are scarce and long term survival rates remain low. Recently, comprehensive genomic studies have highlighted the most commonly altered genes and signaling pathways in this cancer. The Hippo-YAP pathway has been identified as a key oncogenic pathway in multiple tumors. Expression of genes controlled by the Hippo downstream transcriptional coactivators YAP (Yes-associated protein 1) and TAZ (WWTR1, WW domain containing transcription regulator 1) is widely deregulated in human cancer including head and neck squamous cell carcinoma (HNSCC). Interestingly, YAP/TAZ signaling might not be as essential for the normal homeostasis of adult tissues as for oncogenic growth, altogether making the pathway an amenable therapeutic target in cancer. Recent advances in the role of Hippo-YAP pathway in HNSCC have provided evidence that genetic alterations frequent in this type of cancer such as PIK3CA (phosphatidylinositide 3-kinase catalytic subunit alpha) overexpression or FAT1 (FAT atypical cadherin 1) functional loss can result in YAP activation. We discuss current therapeutic options targeting this pathway which are currently in use for other tumor types.
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Hilman, D., and U. Gat. "The Evolutionary History of YAP and the Hippo/YAP Pathway." Molecular Biology and Evolution 28, no. 8 (March 16, 2011): 2403–17. http://dx.doi.org/10.1093/molbev/msr065.
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Zeybek, Naciye Dilara, Eylem Baysal, Ozlem Bozdemir, and Esra Buber. "Hippo Signaling: A Stress Response Pathway in Stem Cells." Current Stem Cell Research & Therapy 16, no. 7 (September 3, 2021): 824–39. http://dx.doi.org/10.2174/1574888x16666210712100002.
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The Hippo pathway, with its core components and the downstream transcriptional coactivators, controls the self-renewable capacity and stemness features of stem cells and serves as a stress response pathway by regulating proliferation, differentiation and apoptosis. The Hippo pathway interaction with other signaling pathways plays an important role in response to various stress stimuli arising from energy metabolism, hypoxia, reactive oxygen species, and mechanical forces. Depending on the energy levels, the Hippo pathway is regulated by AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), which in turn determines stem cell proliferation (cell survival and growth) and differentiation. Oxidative stress-driven by ROS production also affects the Hippo pathway with transcriptional changes through MST/YAP/FoxO pathway and leads to the activation of pro-apoptotic genes and eventually cell death. HIF1alpha/YAP signaling is critical for the long-term maintenance of mesenchymal stem cells (MSCs) under hypoxia. In this review, we present an overview of stem cell response to stress, including mechanical, hypoxia, metabolic and oxidative stress through the modulation of the Hippo pathway. The biological effects such as autophagy, apoptosis and senescence were discussed in the context of the Hippo pathway in stem cells.
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Kim, Youngeun, Wantae Kim, Yonghee Song, Jeong-Rae Kim, Kyungjoo Cho, Hyuk Moon, Simon Weonsang Ro, et al. "Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability." Proceedings of the National Academy of Sciences 114, no. 18 (April 17, 2017): 4691–96. http://dx.doi.org/10.1073/pnas.1620306114.
Full textAbstract:
Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination−deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.
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Kim, Cho-Long, Sue-Hee Choi, and Jung-Soon Mo. "Role of the Hippo Pathway in Fibrosis and Cancer." Cells 8, no. 5 (May 16, 2019): 468. http://dx.doi.org/10.3390/cells8050468.
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The Hippo pathway is the key player in various signaling processes, including organ development and maintenance of tissue homeostasis. This pathway comprises a core kinases module and transcriptional activation module, representing a highly conserved mechanism from Drosophila to vertebrates. The central MST1/2-LATS1/2 kinase cascade in this pathway negatively regulates YAP/TAZ transcription co-activators in a phosphorylation-dependent manner. Nuclear YAP/TAZ bind to transcription factors to stimulate gene expression, contributing to the regenerative potential and regulation of cell growth and death. Recent studies have also highlighted the potential role of Hippo pathway dysfunctions in the pathology of several diseases. Here, we review the functional characteristics of the Hippo pathway in organ fibrosis and tumorigenesis, and discuss its potential as new therapeutic targets.
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Plouffe, Steven W., Audrey W. Hong, and Kun-Liang Guan. "Disease implications of the Hippo/YAP pathway." Trends in Molecular Medicine 21, no. 4 (April 2015): 212–22. http://dx.doi.org/10.1016/j.molmed.2015.01.003.
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Xin, Mei, Yuri Kim, Lillian B. Sutherland, Masao Murakami, Xiaoxia Qi, John McAnally, Enzo R. Porrello, et al. "Hippo pathway effector Yap promotes cardiac regeneration." Proceedings of the National Academy of Sciences 110, no. 34 (August 5, 2013): 13839–44. http://dx.doi.org/10.1073/pnas.1313192110.
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Sugihara, Takaaki, Hajime Isomoto, Gregory Gores, and Rory Smoot. "YAP and the Hippo pathway in cholangiocarcinoma." Journal of Gastroenterology 54, no. 6 (February 27, 2019): 485–91. http://dx.doi.org/10.1007/s00535-019-01563-z.
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Lee, Jihyun, Yujin Jung, Seo won Jeong, Ga Hee Jeong, Gue Tae Moon, and Miri Kim. "Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model." International Journal of Molecular Sciences 22, no. 2 (January 19, 2021): 931. http://dx.doi.org/10.3390/ijms22020931.
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The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.
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Sileo, Pasquale, Clémence Simonin, Patricia Melnyk, Marie-Christine Chartier-Harlin, and Philippe Cotelle. "Crosstalk between the Hippo Pathway and the Wnt Pathway in Huntington’s Disease and Other Neurodegenerative Disorders." Cells 11, no. 22 (November 16, 2022): 3631. http://dx.doi.org/10.3390/cells11223631.
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The Hippo pathway consists of a cascade of kinases that controls the phosphorylation of the co-activators YAP/TAZ. When unphosphorylated, YAP and TAZ translocate into the nucleus, where they mainly bind to the TEAD transcription factor family and activate genes related to cell proliferation and survival. In this way, the inhibition of the Hippo pathway promotes cell survival, proliferation, and stemness fate. Another pathway can modulate these processes, namely the Wnt/β-catenin pathway that is indeed involved in cellular functions such as proliferation and cell survival, as well as apoptosis, growth, and cell renewal. Wnt signaling can act in a canonical or noncanonical way, depending on whether β-catenin is involved in the process. In this review, we will focus only on the canonical Wnt pathway. It has emerged that YAP/TAZ are components of the β-catenin destruction complex and that there is a close relationship between the Hippo pathway and the canonical Wnt pathway. Furthermore, recent data have shown that both of these pathways may play a role in neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, or Amyotrophic Lateral Sclerosis. Thus, this review analyzes the Hippo pathway and the Wnt pathway, their crosstalk, and their involvement in Huntington’s disease, as well as in other neurodegenerative disorders. Altogether, these data suggest possible therapeutic approaches targeting key players of these pathways.