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Qi, Qi, Dean Y. Li, Hongbo R. Luo, Kun-Liang Guan, and Keqiang Ye. "Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability." Proceedings of the National Academy of Sciences 112, no. 23 (May 26, 2015): 7255–60. http://dx.doi.org/10.1073/pnas.1505917112.
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Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control and cancer development. However, how YAP is regulated by extracellular stimuli in tumorigenesis remains incompletely understood. Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity in cancers. Nonetheless, the downstream signaling mediating its oncogenic effects is not well defined. Here we show that netrin-1 via its transmembrane receptors, deleted in colorectal cancer and uncoordinated-5 homolog, up-regulates YAP expression, escalating YAP levels in the nucleus and promoting cancer cell proliferation and migration. Inactivating netrin-1, deleted in colorectal cancer, or uncoordinated-5 homolog B (UNC5B) decreases YAP protein levels, abrogating cancer cell progression by netrin-1, whereas knockdown of mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway, has no effect in blocking netrin-1–induced up-regulation of YAP. Netrin-1 stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence, our findings support that netrin-1 exerts oncogenic activity through YAP signaling, providing a mechanism coupling extracellular signals to the nuclear YAP oncogene.
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Wu, Gaoliang, Chao Hao, Xueliang Qi, and Jianqiang Nie. "Effect of Yes Associated Protein 1 Silence on Proliferation and Apoptosis of Bladder Cancer Cells." Journal of Biomaterials and Tissue Engineering 11, no. 5 (May 1, 2021): 857–63. http://dx.doi.org/10.1166/jbt.2021.2637.
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Yes Associated Protein 1 (YAP) can act as either an oncoprotein or a tumor suppressor in different cellular contexts. However, the reports about the direct role of YAP silence in bladder cancer cells are rare. We designed loss-off-function experiments to investigate the effect of YAP knockdown on bladder cancer cell proliferation, cell cycle and cell apoptosis. We examined YAP expression in human bladder cancer and paracancerous tissues using RT-qPCR, western blot and immunohisto-chemistry. YAP short hairpin RNA (shRNA) was successfully constructed and transfected into T24 cells to knockdown YAP. Cell proliferation, cell cycle and cell apoptosis were analyzed by CCK-8 and flow cytometry. We found the expression levels of YAP mRNA and protein were significantly increased in the bladder cancer tissues when compared with that in the paracancerous tissues. shRNA YAP inhibited cell proliferation, induced cell cycle arrest at G1 phase, and induced cell apoptosis. In conclusion, our findings provided the first evidence that YAP knockdown could inhibit cell proliferation and induce cell apoptosis of bladder cancer cells. YAP inhibition may be beneficial in the treatment of bladder cancer.
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Khan, Kashif, Georges Makhoul, Bin Yu, Adel Schwertani, and Renzo Cecere. "The cytoprotective impact of yes-associated protein 1 after ischemia-reperfusion injury in AC16 human cardiomyocytes." Experimental Biology and Medicine 244, no. 10 (May 29, 2019): 802–12. http://dx.doi.org/10.1177/1535370219851243.
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The Hippo-signaling pathway is a mechanism implicated in cardiomyocyte cytoprotection and regeneration after a myocardial infarction. Yes-associated protein 1, the main effector protein of this pathway, acts as a co-transcriptional activator to promote cardiomyocyte proliferation and survival. However, the biological mechanisms by which yes-associated protein 1 protects the heart post-MI are currently unknown. Here, we propose that yes-associated protein 1 plays a critical role in cardiomyocyte cytoprotection after simulated ischemia-reperfusion injury. AC16 human cardiomyocytes were infected with lentiviral plasmids containing normal human yes-associated protein 1 and a constitutively active form of YAP, YAP1S127A. Cells were exposed to ischemia-reperfusion injury using a hypoxic chamber. Hippo-signaling characterization after ischemia-reperfusion injury was performed via Western blotting and reverse transcriptase polymerase chain reaction. Cell viability, apoptosis, and cellular hypertrophy were assessed as a measure of cytoprotection. The GSK3β inhibitor CHIR99021 was used to investigate cross-talk between Hippo and Wnt-signaling and their role in cytoprotection after ischemia-reperfusion-injury. Ischemia-reperfusion injury resulted in significant decreased expression of the non-phosphorylated Hippo signaling kinases MST1 and LATS1, along with decreased expression of YAP/TAZ. Overexpression of yes-associated protein 1 improved cellular viability, while reducing hypertrophy and apoptosis via the ATM/ATR DNA damage response pathway. Activation of β-catenin in YAP-infected cardiomyocytes synergistically reduced cellular hypertrophy after ischemia-reperfusion-injury. Our findings indicate that yes-associated protein 1 is cytoprotective in AC16 human cardiomyocytes after ischemia-reperfusion injury, which may be mediated by co-activation of the canonical Wnt/β-catenin pathway. Thus, activation of yes-associated protein 1 may be a novel therapeutic to repair the infarcted myocardium. Impact statement Genetically engineering the cells of the heart after myocardial infarction to display a more regenerative phenotype is a promising therapy for heart failure patients. Here, we support a regenerative role for yes-associated protein 1, the main effector protein of the Hippo signaling pathway, in AC16 human cardiomyocytes as a potential therapeutic gene target for cardiac repair after myocardial infarction.
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Irie, Kazuki, Tomoaki Nagai, and Kensaku Mizuno. "Furry protein suppresses nuclear localization of yes-associated protein (YAP) by activating NDR kinase and binding to YAP." Journal of Biological Chemistry 295, no. 10 (January 29, 2020): 3017–28. http://dx.doi.org/10.1074/jbc.ra119.010783.
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The Hippo signaling pathway suppresses cell proliferation and tumorigenesis. In the canonical Hippo pathway, large tumor suppressor kinases 1/2 (LATS1/2) phosphorylate the transcriptional coactivator yes-associated protein (YAP) and thereby suppress its nuclear localization and co-transcriptional activity. Nuclear Dbf2-related kinases 1/2 (NDR1/2), which are closely related to LATS1/2, also phosphorylate and inactivate YAP by suppressing its nuclear localization. Furry (FRY) is a cytoplasmic protein that associates with NDR1/2 and activates them, but its role in the nuclear/cytoplasmic localization of YAP remains unknown. Here, we constructed FRY-knockout cell lines to examine the role of FRY in YAP's cytoplasmic localization. FRY depletion markedly increased YAP nuclear localization and decreased NDR1/2 kinase activity and YAP phosphorylation levels, but did not affect LATS1/2 kinase activity. This indicated that FRY suppresses YAP's nuclear localization by promoting its phosphorylation via NDR1/2 activation. NDR1/2 depletion also promoted YAP nuclear localization, but depletion of both FRY and NDR1/2 increased the number of cells with YAP nuclear localization more strongly than did depletion of NDR1/2 alone, suggesting that FRY suppresses YAP nuclear localization by a mechanism in addition to NDR1/2 activation. Co-precipitation assays revealed that Fry uses its N-terminal 1–2400-amino-acid-long region to bind to YAP. Expression of full-length FRY or its 1–2400 N-terminal fragment restored YAP cytoplasmic localization in FRY-knockout cells. Taken together, these results suggest that FRY plays a crucial role in YAP cytoplasmic retention by promoting YAP phosphorylation via NDR1/2 kinase activation and by binding to YAP, leading to its cytoplasmic sequestration.
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Zhang, Heng, and Shengnan Wu. "Yes-Associated Protein (YAP) Promotes the Nuclear Import of p73." Journal of Physics: Conference Series 277 (January 1, 2011): 012050. http://dx.doi.org/10.1088/1742-6596/277/1/012050.
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Hsu, Ping-Chih, Cheng-Ta Yang, David Jablons, and Liang You. "The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer." Biomedicines 6, no. 4 (December 7, 2018): 114. http://dx.doi.org/10.3390/biomedicines6040114.
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The programmed death-ligand 1(PD-L1)/PD-1 pathway is an immunological checkpoint in cancer cells. The binding of PD-L1 and PD-1 promotes T-cell tolerance and helps tumor cells escape from host immunity. Immunotherapy targeting the PD-L1/PD-1 axis has been developed as an anti-cancer therapy and used in treating advanced human non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Yes-associated protein (YAP) is a key mediator of the Hippo/YAP signaling pathway, and plays important roles in promoting cancer development, drug resistance and metastasis in human NSCLC and MPM. YAP has been suggested as a new therapeutic target in NSCLC and MPM. The role of YAP in regulating tumor immunity such as PD-L1 expression has just begun to be explored, and the correlation between YAP-induced tumorigenesis and host anti-tumor immune responses is not well known. Here, we review recent studies investigating the correlation between YAP and PD-L1 and demonstrating the mechanism by which YAP regulates PD-L1 expression in human NSCLC and MPM. Future work should focus on the interactions between Hippo/YAP signaling pathways and the immune checkpoint PD-L1/PD-1 pathway. The development of new synergistic drugs for immune checkpoint PD-L1/PD-1 blockade in NSCLC and MPM is warranted.
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DAREEN A. MOHAMED, M.D., RANIA A. R. EL-TATAWY, M. D., and YOMNA MAZID EL-HAMD A. NEINAA, M. D. HEBA A.A. EL-BANBI, M.Sc. "Immunohistochemical Expression of Yes-Associated Protein-1 (YAP-1) in Cutaneous Lichen Planus." Medical Journal of Cairo University 87, June (June 10, 2019): 1769–73. http://dx.doi.org/10.21608/mjcu.2019.53963.
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Sharifi-Sanjani, Maryam, Mariah Berman, Dmitry Goncharov, Mohammad Alhamaydeh, Theodore Guy Avolio, Jeffrey Baust, Baojun Chang, et al. "Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation." International Journal of Molecular Sciences 22, no. 11 (June 7, 2021): 6164. http://dx.doi.org/10.3390/ijms22116164.
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Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.
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Pilgrim, Adeiye A., Hunter C. Jonus, Andrew Ho, Anna Cole, Jenny Shim, and Kelly C. Goldsmith. "Abstract 3545: The Yes-associated protein (YAP) regulates GD2 immunotherapy response in high-risk neuroblastoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3545. http://dx.doi.org/10.1158/1538-7445.am2023-3545.
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Abstract Background Patients with the pediatric solid tumor high-risk neuroblastoma (HR NB) receive intense multimodal therapy yet 50% still relapse with chemotherapy-resistant disease. Relapsed NBs harbor increased RAS/MAPK pathway mutations and increased expression and downstream activity of the transcriptional co-regulator YAP. We have previously shown that YAP mediates resistance to chemotherapy and MEK inhibitors in RAS mutant NBs (Shim et al., Cancer Res 2020). Patients with relapsed NB are treated with the GD2-targeting monoclonal antibody dinutuximab in combination with chemotherapy. Given the increased expression and activity of YAP in relapsed HR NB, we posited that YAP might also play a role in GD2 immunotherapy response. Methods/Results We stably knocked down YAP in the human derived NRAS mutant SK-N-AS NB cell line with a scrambled short hairpin (sh) control or 2 YAP-targeting shRNAs to generate 3 distinct cell lines. Dinutuximab requires antibody-dependent cellular cytotoxicity (ADCC) and we have shown that gamma delta (γδ) T cells augment dinutuximab in aggressive NB models. We exposed the shYAP1, shYAP2, and control SK-N-AS cells to γδ T cells with/without dinutuximab. YAP knockdown sensitized both SK-N-AS shYAP cell lines to γδ T cell killing both in the presence and absence of dinutuximab. To investigate the mechanism of increased dinutuximab sensitivity, we evaluated a panel of NB cell lines (MYCN amplified and MYCN single copy) for YAP protein and GD2 cell surface expression and noted an inverse relationship. That same inverse correlation was found for GD2 and YAP gene expression in primary HR NB tumor datasets. We therefore evaluated GD2 expression following YAP knockdown in SK-N-AS and show that GD2 significantly increased on the cell surface following YAP inhibition. PRRX1 is a master transcription factor that induces a mesenchymal NB phenotype which is one of high YAP expression with very low to no GD2 surface expression. Interestingly, PRRX1 expression increased in YAP knockdown cells yet GD2 expression also increased, suggesting YAP regulates GD2 expression more directly than PRRX1. In the GD2 biosynthesis pathway, GM3 is converted into GD3 by GD3 synthase (GD3S). GD2 synthase then catalyzes GD3 into GD2. GD3S gene (ST8SIA1) expression significantly increased (>100-fold) upon YAP knockdown. Furthermore, shRNA stable inhibition of GD3S in shYAP NB cells reverted the phenotype and decreased GD2 cell surface expression back to baseline. We then treated established SK-N-AS control or shYAP xenografts with an 18-day course of human γδ T cells, dinutuximab, and cyclophosphamide. Pilot results show significantly extended survival in mice harboring SK-N-AS shYAP tumors. Conclusion These results support YAP regulation of GD2 expression through transcriptional suppression of GD3 synthase and identify YAP as a therapeutic target to augment GD2 immunotherapy responses in HR and relapsed NB. Citation Format: Adeiye A. Pilgrim, Hunter C. Jonus, Andrew Ho, Anna Cole, Jenny Shim, Kelly C. Goldsmith. The Yes-associated protein (YAP) regulates GD2 immunotherapy response in high-risk neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3545.
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Venkatasubramanian, Gomathi, Devaki A. Kelkar, Susmita Mandal, Mohit Kumar Jolly, and Madhura Kulkarni. "Analysis of Yes-Associated Protein-1 (YAP1) Target Gene Signature to Predict Progressive Breast Cancer." Journal of Clinical Medicine 11, no. 7 (March 31, 2022): 1947. http://dx.doi.org/10.3390/jcm11071947.
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Breast cancers are treated according to the ER/PR or HER2 expression and show better survival outcomes with targeted therapy. Triple-negative breast cancers (TNBCs) with a lack of expression of ER/PR and HER2 are treated with systemic therapy with unpredictable responses and outcomes. It is essential to investigate novel markers to identify targeted therapies for TNBC. One such marker is YAP1, a transcription co-activator protein that shows association with poor prognosis of breast cancer. YAP1 transcriptionally regulates the expression of genes that drive the oncogenic phenotypes. Here, we assess a potential YAP target gene signature to predict a progressive subset of breast tumors from METABRIC and TCGA datasets. YAP1 target genes were shortlisted based on expression correlation and concordance with YAP1 expression and significant association with survival outcomes of patients. Hierarchical clustering was performed for the shortlisted genes. The utility of the clustered genes was assessed by survival analysis to identify a recurring subset. Expression of the shortlisted target genes showed significant association with survival outcomes of HER2-positive and TNBC subset in both datasets. The shortlisted genes were verified using an independent dataset. Further validation using IHC can prove the utility of this potential prognostic signature to identify a recurrent subset of HER2-positive and TNBC subtypes.
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Kim, Seon-Young, Song-Yi Park, Hwan-Seok Jang, Yong-Doo Park, and Sun-Ho Kee. "Yes-Associated Protein Is Required for ZO-1-Mediated Tight-Junction Integrity and Cell Migration in E-Cadherin-Restored AGS Gastric Cancer Cells." Biomedicines 9, no. 9 (September 18, 2021): 1264. http://dx.doi.org/10.3390/biomedicines9091264.
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Yes-associated protein (YAP) regulates numerous cellular homeostasis processes and malignant transformation. We found that YAP influences ZO-1-mediated cell migration using E-cadherin-restored EC96 cells derived from gastric malignant AGS cells. Ectopic expression of E-cadherin enhanced straightforward migration of cells, in comparison to the meandering movement of parental AGS cells. In EC96 cells, YAP and ZO-1 expression increased but nuclear YAP levels and activity were reduced. Nuclear factor-κB (NF-κB) mediated the increase in ZO-1 expression, possibly stabilizing cytoplasmic YAP post-translationally. Downregulation of YAP expression using siYAP RNA or stable knock-down inhibited straightforward cell migration by fragmenting ZO-1 containing tight junctions (TJs) but not adherens junctions, implying involvement of YAP in ZO-1-mediated cell migration. The association of YAP with ZO-1 was mediated by angiomotin (AMOT) because downregulation of AMOT dissociated YAP from ZO-1 and reduced cell migration. E-cadherin restoration in malignant cancer cells induced NF-κB signaling to enhance ZO-1 expression and subsequently stabilize YAP. At high expression levels, YAP associates with ZO-1 via AMOT at TJs, influencing ZO-1-mediated cell migration and maintaining TJ integrity.
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Kim, Hae-Young, Gaurav Agrahari, Min Jung Lee, Lee-Jung Tak, Won-Kook Ham, and Tae-Yoon Kim. "Low-Temperature Argon Plasma Regulates Skin Moisturizing and Melanogenesis-Regulating Markers through Yes-Associated Protein." International Journal of Molecular Sciences 22, no. 4 (February 14, 2021): 1895. http://dx.doi.org/10.3390/ijms22041895.
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Extensive water loss and melanin hyperproduction can cause various skin disorders. Low-temperature argon plasma (LTAP) has shown the possibility of being used for the treatment of various skin diseases, such as atopic dermatitis and skin cancer. However, the role of LTAP in regulating skin moisturizing and melanogenesis has not been investigated. In this study, we aimed to determine the effect of LTAP on yes-associated protein (YAP), a major transcriptional coactivator in the Hippo signaling pathway that is involved in skin moisturizing and melanogenesis-regulating markers. In normal human epidermal keratinocytes (NHEKs), the human epidermal keratinocyte line HaCaT, and human dermal fibroblasts (HDFs), we found that LTAP exhibited increased expression levels of YAP protein. In addition, the expression levels of filaggrin (FLG), which is involved in natural moisturizing factors (NMFs), and hyaluronic acid synthase (HAS), transglutaminase (TGM), and involucrin (IVL), which regulate skin barrier and moisturizing, were also increased after exposure to LTAP. Furthermore, collagen type I alpha 1 and type III alpha 1 (COL1A1, COL3A1) were increased after LTAP exposure, but the expression level of matrix metalloproteinase-3 (MMP-3) was reduced. Moreover, LTAP was found to suppress alpha-melanocyte stimulating hormone (α-MSH)-induced melanogenesis in murine melanoma B16F10 cells and normal human melanocytes (NHEMs). LTAP regulates melanogenesis of the melanocytes through decreased YAP pathway activation in a melanocortin 1 receptor (MC1R)-dependent manner. Taken together, our data show that LTAP regulates skin moisturizing and melanogenesis through modulation of the YAP pathway, and the effect of LTAP on the expression level of YAP varies from cell to cell. Thus, LTAP might be developed as a treatment method to improve the skin barrier, moisture content, and wrinkle formation, and to reduce melanin generation.
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Turpo-Peqqueña, Albert, Sebastian Luna-Prado, Renato Valencia-Arce, Fabio Del-Carpio-Carrazco, and Badhin Gómez. "A Theoretical Study on the Efficacy and Mechanism of Combined YAP-1 and PARP-1 Inhibitors in the Treatment of Glioblastoma Multiforme Using Peruvian Maca Lepidium meyenii." Current Issues in Molecular Biology 47, no. 1 (January 9, 2025): 40. https://doi.org/10.3390/cimb47010040.
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Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant forms of brain cancer. Current therapeutic strategies, including surgery, chemotherapy, and radiotherapy, often fail due to the tumor’s ability to develop resistance. The proteins YAP-1 (Yes-associated protein 1) and PARP-1 (Poly-(ADP-ribose)–polymerase-1) have been implicated in this resistance, playing crucial roles in cell proliferation and DNA repair mechanisms, respectively. This study explored the inhibitory potential of natural compounds from Lepidium meyenii (Peruvian Maca) on the YAP-1 and PARP-1 protein systems to develop novel therapeutic strategies for GBM. By molecular dynamics simulations, we identified N-(3-Methoxybenzyl)-(9Z,12Z,15Z)- octadecatrienamide (DK5) as the most promising natural inhibitor for PARP-1 and stearic acid (GK4) for YAP-1. Although synthetic inhibitors, such as Olaparib (ODK) for PARP-1 and Verteporfin (VER) for YAP-1, only VER was superior to the naturally occurring molecule and proved a promising alternative. In conclusion, natural compounds from Lepidium meyenii (Peruvian Maca) offer a potentially innovative approach to improve GBM treatment, complementing existing therapies with their inhibitory action on PARP-1 and YAP-1.
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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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Park, Sangryong, Ho-Young Lee, Jayoung Kim, Hansol Park, Young Seok Ju, Eung-Gook Kim, and Jaehong Kim. "Cerebral Cavernous Malformation 1 Determines YAP/TAZ Signaling-Dependent Metastatic Hallmarks of Prostate Cancer Cells." Cancers 13, no. 5 (March 5, 2021): 1125. http://dx.doi.org/10.3390/cancers13051125.
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Enhanced Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling is correlated with the extraprostatic extension of prostate cancer. However, the mechanism by which YAP/TAZ signaling becomes hyperactive and drives prostate cancer progression is currently unclear. In this study, we revealed that higher expression of CCM1, which is uniquely found in advanced prostate cancer, is inversely correlated with metastasis-free and overall survival in patients with prostate cancer. We also demonstrated that CCM1 induces the metastasis of multiple types of prostate cancer cells by regulating YAP/TAZ signaling. Mechanistically, CCM1, a gene mutated in cerebral cavernous malformation, suppresses DDX5, which regulates the suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. Our findings highlight the importance of CCM1-DDX5-YAP/TAZ signaling in the metastasis of prostate cancer cells.
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Konishi, Takanori, Rebecca M. Schuster, and Alex B. Lentsch. "Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 4 (April 1, 2018): G471—G482. http://dx.doi.org/10.1152/ajpgi.00153.2017.
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Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size; however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells. The Hippo pathway components, large tumor suppressor 1 (LATS1) and its adapter protein, Mps one binder 1 (MOB1), were inactivated during liver repair, and YAP and TAZ were activated selectively in hepatic stellate cells. Concurrently, the expression of connective tissue growth factor and survivin, both of which are YAP and TAZ target genes, were upregulated. Hepatic stellate cell expansion and concomitant activation of YAP and TAZ occurred only in the injured liver and were not observed in the nonischemic liver. Treatment of mice with verteporfin, an inhibitor of YAP and TAZ, decreased hepatic stellate cell proliferation, survivin, and cardiac ankyrin repeat protein expression. These changes were associated with a significant decrease in hepatocyte proliferation. The data suggest that liver repair and regeneration after I/R injury are dependent on hepatic stellate cell proliferation, which is mediated by YAP and TAZ. NEW & NOTEWORTHY This study is the first to assess the proliferation of hepatic stellate cells (HSCs) after ischemia-reperfusion (I/R) injury and their role in the reparative and regenerative process. Here we show that the Hippo pathway is inactivated after I/R and that Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation is detected in HSC. HSC proliferation and expansion are prominent during liver recovery after I/R injury. Inhibition of YAP/TAZ activation with verteporfin reduces HSC proliferation and target gene expression and attenuates hepatocyte proliferation.
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Zhou, Ruyuan, Qirou Wu, Mengqiu Wang, Seema Irani, Xiao Li, Qian Zhang, Fansen Meng, et al. "The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration." PLOS Biology 19, no. 2 (February 25, 2021): e3001122. http://dx.doi.org/10.1371/journal.pbio.3001122.
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The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.
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Liao, Jiujiang, Yangxi Zheng, Mingyu Hu, Ping Xu, Li Lin, Xiyao Liu, Yue Wu, et al. "Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations." Hypertension 79, no. 2 (February 2022): 399–412. http://dx.doi.org/10.1161/hypertensionaha.121.18363.
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Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling–dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.
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Liu, Lu, Cui Zhai, Yilin Pan, Yanting Zhu, Wenhua Shi, Jian Wang, Xin Yan, et al. "Sphingosine-1-phosphate induces airway smooth muscle cell proliferation, migration, and contraction by modulating Hippo signaling effector YAP." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 4 (October 1, 2018): L609—L621. http://dx.doi.org/10.1152/ajplung.00554.2017.
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Sphingosine-1-phosphate (S1P), a bioactive lipid, has been shown to be elevated in the airways of individuals with asthma and modulates the airway smooth muscle cell (ASMC) functions, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue. S1P induced yes-associated protein (YAP) dephosphorylation and nuclear localization via the S1PR2/3/Rho-associated protein kinase (ROCK) pathway, and this in turn increased forkhead box M1 (FOXM1) and cyclin D1 expression leading to ASMC proliferation, migration, and contraction. Pretreatment of cells with S1PR2 antagonist JTE013, S1PR3 antagonist CAY10444, or ROCK inhibitor Y27632 blocked S1P-induced alterations of YAP, FOXM1, cyclin D1, and ASMC proliferation, migration, and contraction. In addition, prior silencing of YAP or FOXM1 with siRNA reversed the effect of S1P on ASMC functions. Taken together, our study indicates that S1P stimulates ASMC proliferation, migration, and contraction by binding to S1PR2/3 and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma.
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Ngo, Mai-Huong T., Sue-Wei Peng, Yung-Che Kuo, Chun-Yen Lin, Ming-Heng Wu, Chia-Hsien Chuang, Cheng-Xiang Kao, et al. "A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma." Cancers 13, no. 15 (July 29, 2021): 3812. http://dx.doi.org/10.3390/cancers13153812.
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The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.
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Wesener, Marie C., Sofia M. E. Weiler, Michaela Bissinger, Tobias F. Klessinger, Fabian Rose, Sabine Merker, Marcin Luzarowski, et al. "CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer." International Journal of Molecular Sciences 25, no. 15 (August 5, 2024): 8549. http://dx.doi.org/10.3390/ijms25158549.
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The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients.
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Symons, R., F. Colella, F. Collins, A. Roelofs, and C. De Bari. "OP0036 IL-6 ACTIVATES YES-ASSOCIATED PROTEIN (YAP) IN FIBROBLASTS AND INDUCES YAP-SNAIL COMPLEX FORMATION TO DRIVE SYNOVIAL LINING PATHOLOGY IN INFLAMMATORY ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 19.1–19. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2530.
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Background:In rheumatoid arthritis (RA), the fibroblast-like synoviocytes (FLS) in synovial lining become invasive and cause joint destruction. The molecular mechanisms underpinning this pathogenic FLS phenotype are incompletely understood. The FLS descend from Growth differentiation factor 5 (Gdf5)-expressing joint interzone cells in the embryo, and we showed that conditional ablation of the transcriptional co-activator Yes associated protein (Yap) in Gdf5-lineage cells prevents synovial lining hyperplasia after traumatic cartilage injury in mice [1].Objectives:Here, we investigated a potential role for Yap in pathogenic FLS in immune-mediated inflammatory arthritis.Methods:Immunohistochemistry was used to detect Yap in human RA synovium and Yap, Snail and Ctgf in mouse synovium following antigen-induced arthritis (AIA). To determine the effect of Yap knockout (KO) in synovial stromal cells, AIA was induced in Gdf5-Cre;tdTomato;Yapfl/fl (Yap cKO) and Gdf5-Cre;tdTomato;Yapwt/wt (control) mice, or in Pdgfrα-CreER;Yapfl/fl (Yap ciKO, targeting Pdgfrα-expressing fibroblasts) and Yapfl/fl or YapWT/fl (control) mice after adult tamoxifen induction. Yap KO in both models was confirmed by immunohistochemistry. After nine days, arthritis severity was determined by histological scoring of synovial lining hyperplasia, immune infiltrates, cellular exudate, and marginal erosions. TdTomato+ Gdf5-lineage cells in synovium were quantified. In vitro, Yap reporter cells were treated with inflammatory cytokines to evaluate their ability to stimulate Yap-induced GFP expression by flow cytometry. Snail overexpression, siRNA-mediated Yap knockdown, and IL-6/sIL-6R stimulation were performed on normal mouse FLS, AIA-FLS or human RA-FLS, and cell invasion through a matrigel-coated transwell was quantified. A proximity ligation assay was utilised to detect Yap/Snail complex formation.Results:Average expression levels of Yap (p<0.0001), its transcription factor partner Snail (p=0.002), and their downstream target Ctgf (p=0.0003), were increased in mouse synovium after AIA (n=5), and Yap was highly expressed by FLS in human RA synovium. Yap cKO mice (n=24) showed a significantly decreased arthritis severity (p=0.002) after AIA compared to controls (n=22), with significant reductions in synovial lining hyperplasia (p<0.001), synovial immune cell infiltrates (p=0.026) and marginal erosions (p=0.002). Similarly, Yap ciKO mice (n=6) showed a significant decrease in arthritis score (p=0.039) after AIA compared to controls (n=9). However, both control mice (p<0.001) and Yap cKO mice (p<0.001) showed an extensive expansion of tdTomato+ Gdf5-lineage synovial cells after AIA, with no significant difference between control and Yap cKO mice. In vitro, Yap knockdown prevented IL-6/sIL-6R-induced invasion of normal mouse FLS (p=0.037) and decreased the invasiveness of AIA-FLS (p=0.0057). Using Yap reporter cells, we found that Yap was activated by IL-6/sIL-6R (p=0.016), but not TNFα or IL-1β. Finally, IL-6/sIL-6R treatment of normal mouse FLS (p=0.033) or human RA-FLS (p=0.036) induced Yap-Snail complex formation, and Yap knockdown prevented FLS invasion induced by Snail overexpression (p=0.027).Conclusion:These data demonstrate that via activation by IL-6, and co-operation with the transcription factor Snail, Yap acts as a key modulator of the invasive and destructive phenotype of FLS in inflammatory arthritis. Therapeutic targeting of Yap could reduce joint destruction in RA.References:[1]A. J. Roelofs et al., “Joint morphogenetic cells in the adult mammalian synovium,” Nat. Commun., vol. 8, no. May, p. 15040, 2017. DOI: 10.1136/annrheumdis-2018-213799Acknowledgements:This work was funded by the Medical Research Council (MR/L020211/1 and MR/L022893/1) and Versus Arthritis (20775 and 21156).Disclosure of Interests:None declared
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Yoo, Geon, Dongil Park, Yoonjoo Kim, and Chaeuk Chung. "New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development." Cancers 13, no. 12 (June 20, 2021): 3069. http://dx.doi.org/10.3390/cancers13123069.
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Despite significant innovations in lung cancer treatment, such as targeted therapy and immunotherapy, lung cancer is still the principal cause of cancer-associated death. Novel strategies to overcome drug resistance and inhibit metastasis in cancer are urgently needed. The Hippo pathway and its effector, Yes-associated protein (YAP), play crucial roles in lung development and alveolar differentiation. YAP is known to mediate mechanotransduction, an important process in lung homeostasis and fibrosis. In lung cancer, YAP promotes metastasis and confers resistance against chemotherapeutic drugs and targeted agents. Recent studies revealed that YAP directly controls the expression of programmed death-ligand 1 (PD-L1) and modulates the tumor microenvironment (TME). YAP not only has a profound relationship with autophagy in lung cancer but also controls alveolar differentiation, and is responsible for tubular structure formation in lung organoids. In this review, we discuss the various roles and clinical implications of YAP in lung cancer and propose that targeting YAP can be a promising strategy for treating lung cancer.
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Huang, Chen, Wenwen Zhang, and Yuelin Zhu. "Drug-eluting stent specifically designed to target vascular smooth muscle cell phenotypic modulation attenuated restenosis through the YAP pathway." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 3 (September 1, 2019): H541—H551. http://dx.doi.org/10.1152/ajpheart.00089.2019.
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Vascular smooth muscle cell (SMC) phenotypic modulation contributes to the development of restenosis. A sorafenib-eluting stent was specifically designed to target SMC phenotypic modulation to inhibit in-stent restenosis in the present study. SMC contractile protein from the freshly isolated rat aorta was expressed at a high level, but its expression was dramatically reduced after SMCs were cultured in 10% FBS for 1 wk. After sorafenib treatment, SMC contractile protein expression was markedly upregulated. We further observed that Yes-associated protein (YAP) expression was attenuated after sorafenib treatment in a dose-dependent manner. Overexpression of YAP by lentivirus reversed the expression of sorafenib-induced SMC contractile protein and increased the expression of cyclin D. Mechanistically, sorafenib regulated the serum response factor-myocardin (SRF-Myocd) complex through competitive binding of YAP to Myocd and increased SRF binding to CArG-containing regions of SMC-specific contractile genes within intact chromatin, thereby controlling the activity of smooth muscle-specific gene transcription. In a rabbit carotid model, the sorafenib-eluting stent (SFES) dramatically inhibited in-stent restenosis and upregulated SMC contractile protein expression. Overexpression of YAP blocked the antirestenosis effect of SFES and repressed contractile smooth muscle-specific genes in vivo, indicating that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. We demonstrated that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. Targeting SMC phenotypic modulation by drug-eluting stent represents an attractive therapeutic approach for the treatment of occlusive vascular diseases. NEW & NOTEWORTHY In the present study, we demonstrated that sorafenib regulates smooth muscle cell (SMC) phenotypic modulation from a proliferative to a contractile state. Sorafenib induced a myocardin-serum response factor interaction and increased SMC contractile gene transcription through the Yes-associated protein pathway. Moreover, local delivery of sorafenib regulating SMC phenotypic modulation represents a promising strategy in the design of drug-eluting stents.
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Laiman, Vincent, Didik Setyo Heriyanto, Yueh-Lun Lee, Ching-Huang Lai, Chih-Hong Pan, Wei-Liang Chen, Chung-Ching Wang, Kai-Jen Chuang, Jer-Hwa Chang, and Hsiao-Chi Chuang. "Zinc Oxide Nanoparticles Promote YAP/TAZ Nuclear Localization in Alveolar Epithelial Type II Cells." Atmosphere 13, no. 2 (February 16, 2022): 334. http://dx.doi.org/10.3390/atmos13020334.
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We investigated roles of Hippo signaling pathway components in alveolar type II cells (AECII) after zinc oxide nanoparticle (ZnONP) exposure. ZnONPs physicochemistry was characterized using field emission-scanning electron microscopy (FE-SEM) and energy-dispersive X-ray (EDX) microanalysis. ZnONP deposition in human respiratory tract was estimated using multiple-path particle dosimetry (MPPD) model. MLE-12 AECII were cultured and exposed to 0, 1, and 5 μg/mL of ZnONPs for 24 h. Western blots were used to investigate signaling pathways associated with Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), cell adherens junctions, differentiation, and senescence. ZnONPs morphology was irregular, with Zn and O identified. Approximately 72% of inhaled ZnONPs were deposited in lungs, with 26% being deposited in alveolar regions. ZnONP exposure increased nuclear YAP expression and decreased cytoplasmic YAP expression by AECII. Adherens junction proteins, E-cadherin, α-catenin, and β-catenin, on AECII decreased after ZnONP exposure. ZnONP exposure of AECII increased alveolar type I (AECI) transition protein, LGALS3, and the AECI protein, T1α, while decreasing AECII SPC expression. ZnONP exposure induced Sirt1 and p53 senescence proteins by AECII. Our findings showed that inhalable ZnONPs can deposit in alveoli, which promotes YAP nuclear localization in AECII, resulting in decrease tight junctions, cell differentiation, and cell senescence.
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Liang, Ning, Chi Zhang, Patricia Dill, Ganna Panasyuk, Delphine Pion, Vonda Koka, Morgan Gallazzini, et al. "Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex." Journal of Experimental Medicine 211, no. 11 (October 6, 2014): 2249–63. http://dx.doi.org/10.1084/jem.20140341.
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Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.
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Fan, Ye, Yangjuan Gao, Jianhua Rao, Ke Wang, Feng Zhang, and Chuanyong Zhang. "YAP-1 Promotes Tregs Differentiation in Hepatocellular Carcinoma by Enhancing TGFBR2 Transcription." Cellular Physiology and Biochemistry 41, no. 3 (2017): 1189–98. http://dx.doi.org/10.1159/000464380.
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Background/Aims: Immunosuppression is one of the hallmarks of cancer; however, its molecular mechanism remains unknown. In the present study, we sought to investigate the expression and activation of yes-associated protein 1 (YAP-1) and its roles in T cells within hepatocellular carcinoma (HCC). Methods: The expression and activation of YAP-1 were accessed by real-time PCR, immunohistochemistry staining, western blot, and flow cytometry. The potential regulation effect of YAP-1 on Regulatory T cells (Tregs) differentiation was predicted using bioinformatics tools and verified by in vitro studies. Results: Significant overexpression and activation of YAP-1 was detected within peripheral blood mononuclear cells and showed positive linear correlation to Treg percentage; it may serve as a valuable indicator of a bad prognosis. Using in vitro studies, we found that overexpression and activation of YAP-1 can promote naïve T cell polarization stimulation to Tregs by increasing the expression of TGFBR2. The YAP-1/TEADs DNA binding site was spotted within the promoter region of TGFBR2 and related to its transcription activity. YAP-1 acted as a co-activator of TGFBR2 transcription by binding directly to the TGFBR2 promoter through TEADs. Conclusion: Overexpression and activation of YAP-1 in HCC T cells can induce immunosuppression by promoting Treg differentiation via transcriptional enhancement of TGFBR2.
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Yamashiro, Yoshito, Bui Quoc Thang, Karina Ramirez, Seung Jae Shin, Tomohiro Kohata, Shigeaki Ohata, Tram Anh Vu Nguyen, Sumio Ohtsuki, Kazuaki Nagayama, and Hiromi Yanagisawa. "Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling." Proceedings of the National Academy of Sciences 117, no. 18 (April 22, 2020): 9896–905. http://dx.doi.org/10.1073/pnas.1919702117.
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The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix–cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin β1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.
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Uttagomol, Jutamas, Usama Sharif Ahmad, Ambreen Rehman, Yunying Huang, Ana C. Laly, Angray Kang, Jan Soetaert, et al. "Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces." International Journal of Molecular Sciences 20, no. 24 (December 10, 2019): 6221. http://dx.doi.org/10.3390/ijms20246221.
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Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in the expression and localization of junction assembly proteins. The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of yes-associated protein (YAP), a mechanosensory, and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to the strain or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. Plakophilin 1 (PKP1) seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected Dsg3 junctional assembly with concomitant loss of phospho-YAP at the cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.
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Rigiracciolo, Damiano Cosimo, Nijiro Nohata, Rosamaria Lappano, Francesca Cirillo, Marianna Talia, Domenica Scordamaglia, J. Silvio Gutkind, and Marcello Maggiolini. "IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells." Cells 9, no. 4 (April 18, 2020): 1010. http://dx.doi.org/10.3390/cells9041010.
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Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.
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Kitagawa, Koh, Kei Moriya, Kosuke Kaji, Soichiro Saikawa, Shinya Sato, Norihisa Nishimura, Tadashi Namisaki, Takemi Akahane, Akira Mitoro, and Hitoshi Yoshiji. "Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells." International Journal of Molecular Sciences 21, no. 20 (October 14, 2020): 7588. http://dx.doi.org/10.3390/ijms21207588.
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Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker BAX and downregulating the anti-apoptotic markers MCL1 and BCL2. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes CTGF, CYR61, ANKRD1, and MFAP5 in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA.
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Elkholy, Shimaa, Aya Abdelbary, Dina Elazab, Mohamed Elkablawy, and Asmaa G. Abdou. "The Prognostic Impact of SIRT1, STAT3, and YAP1 in Colorectal Carcinoma." Applied Immunohistochemistry & Molecular Morphology 33, no. 1 (December 5, 2024): 29–42. https://doi.org/10.1097/pai.0000000000001234.
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Colorectal cancer (CRC) is the most common gastrointestinal malignancy with a complicated behavior including relapse, metastasis, and development of resistance to chemotherapeutic drugs. Silent information regulator 2 homologue 1 (SIRT1), signal transducer and activator of transcription 3 (STAT3), and yes-associated protein (YAP) are cancer-related genes that have unclarified actions and even controversial roles in many human cancers including CRC. The current study aimed to evaluate the prognostic roles of SIRT1, STAT3, and YAP in CRC. Hundred and 13 CRC archival blocks were processed by TMA technique and immunostained with SIRT1, STAT3, and YAP antibodies. SIRT1, STAT3, and YAP are expressed in both tumor and stromal cells. SIRT1 expression in both the epithelial and stromal compartments was associated with favorable prognostic parameters, including longer overall and recurrence-free survival. In contrast, the epithelial and stromal expression of both STAT3 and YAP1 was associated with poor prognostic parameters, including short overall and recurrence-free survival. STAT3 and YAP epithelial expression showed a positive correlation with one another, but a negative correlation with epithelial SIRT1. While SIRT1 stromal expression was inversely correlated with stromal YAP expression, STAT3 and YAP concurrent stromal expression demonstrated a positive correlation with one another. There is crosstalk between CRC tumor and stromal cells by the coparallel expression of molecules such as SIRT1, STAT3, and YAP. There is a synergism between the STAT3 and YAP pathways in CRC at the level of the tumor and stroma. The tumor microenvironment of CRC could modulate tumor behavior by expressing markers suppressing invasion, such as SIRT1 or enhancing invasion, such as STAT3 and YAP.
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Nilsson, Monique B., Huiying Sun, Jacqulyne Robichaux, Matthias Pfeifer, Ultan McDermott, Jon Travers, Lixia Diao, et al. "A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components." Science Translational Medicine 12, no. 559 (September 2, 2020): eaaz4589. http://dx.doi.org/10.1126/scitranslmed.aaz4589.
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Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which resistance emerges through EGFR-independent mechanisms, such as through pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis as a driver of EMT-associated EGFR TKI resistance. EGFR inhibitor resistance was associated with broad multidrug resistance that extended across multiple chemotherapeutic and targeted agents, consistent with the difficulty of effectively treating resistant disease. EGFR TKI–resistant cells displayed increased abundance of spindle assembly checkpoint (SAC) proteins, including polo-like kinase 1 (PLK1), Aurora kinases, survivin, and kinesin spindle protein (KSP). Moreover, EGFR TKI–resistant cells exhibited vulnerability to SAC inhibitors. Increased activation of the YAP/FOXM1 axis mediated an increase in the abundance of SAC components in resistant cells. The clinical relevance of these finding was indicated by evaluation of specimens from patients with EGFR mutant lung cancer, which showed that high FOXM1 expression correlated with expression of genes encoding SAC proteins and was associated with a worse clinical outcome. These data revealed the YAP/FOXM1 axis as a central regulator of EMT-associated EGFR TKI resistance and that this pathway, along with SAC components, are therapeutic vulnerabilities for targeting this multidrug-resistant phenotype.
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Daoud, Fatima, Marycarmen Arévalo Martinez, Johan Holmberg, Azra Alajbegovic, Neserin Ali, Catarina Rippe, Karl Swärd, and Sebastian Albinsson. "YAP and TAZ in Vascular Smooth Muscle Confer Protection Against Hypertensive Vasculopathy." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 4 (April 2022): 428–43. http://dx.doi.org/10.1161/atvbaha.121.317365.
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Background: Hypertension remains a major risk factor for cardiovascular diseases, but the underlying mechanisms are not well understood. We hypothesize that appropriate mechanotransduction and contractile function in vascular smooth muscle cells are crucial to maintain vascular wall integrity. The Hippo pathway effectors YAP (yes-associated protein 1) and TAZ (WW domain containing transcription regulator 1) have been identified as mechanosensitive transcriptional coactivators. However, their role in vascular smooth muscle cell mechanotransduction has not been investigated in vivo. Methods: We performed physiological and molecular analyses utilizing an inducible smooth muscle–specific YAP/TAZ knockout mouse model. Results: Arteries lacking YAP/TAZ have reduced agonist-mediated contraction, decreased myogenic response, and attenuated stretch-induced transcriptional regulation of smooth muscle markers. Moreover, in established hypertension, YAP/TAZ knockout results in severe vascular lesions in small mesenteric arteries characterized by neointimal hyperplasia, elastin degradation, and adventitial thickening. Conclusions: This study demonstrates a protective role of YAP/TAZ against hypertensive vasculopathy.
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Zhang, Qiong, Xujun Zhang, Xiaobo Lei, Hai Wang, Jingjing Jiang, Yuchong Wang, Kefan Bi, and Hongyan Diao. "Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response." PLOS Pathogens 18, no. 5 (May 3, 2022): e1010505. http://dx.doi.org/10.1371/journal.ppat.1010505.
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The Hippo signaling pathway, which is historically considered as a dominator of organ development and homeostasis has recently been implicated as an immune regulator. However, its role in host defense against influenza A virus (IAV) has not been widely investigated. Here, we found that IAV could activate the Hippo effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through physical binding of the IAV non-structural protein 1 (NS1) with C-terminal domain of YAP/TAZ, facilitating their nuclear location. Meanwhile, YAP/TAZ downregulated the expression of pro-inflammatory and anti-viral cytokines against IAV infection, therefore benefiting virus replication and host cell apoptosis. A mouse model of IAV infection further demonstrated Yap deficiency protected mice against IAV infection, relieving lung injury. Mechanistically, YAP/TAZ blocked anti-viral innate immune signaling via downregulation of Toll-like receptor 3 (TLR3) expression. YAP directly bound to the putative TEADs binding site on the promoter region of TLR3. The elimination of acetylated histone H3 occupancy in the TLR3 promoter resulted in its transcriptional silence. Moreover, treatment of Trichostatin A, a histone deacetylases (HDACs) inhibitor or disruption of HDAC4/6 reversed the inhibition of TLR3 expression by YAP/TAZ, suggesting HDAC4/6 mediated the suppression function of YAP/TAZ. Taken together, we uncovered a novel immunomodulatory mechanism employed by IAV, where YAP/TAZ antagonize TLR3-mediated innate immunity.
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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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Damkham, Nattaya, Surapol Issaragrisil, and Chanchao Lorthongpanich. "Role of YAP as a Mechanosensing Molecule in Stem Cells and Stem Cell-Derived Hematopoietic Cells." International Journal of Molecular Sciences 23, no. 23 (November 23, 2022): 14634. http://dx.doi.org/10.3390/ijms232314634.
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Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ) are transcriptional coactivators in the Hippo signaling pathway. Both are well-known regulators of cell proliferation and organ size control, and they have significant roles in promoting cell proliferation and differentiation. The roles of YAP and TAZ in stem cell pluripotency and differentiation have been extensively studied. However, the upstream mediators of YAP and TAZ are not well understood. Recently, a novel role of YAP in mechanosensing and mechanotransduction has been reported. The present review updates information on the regulation of YAP by mechanical cues such as extracellular matrix stiffness, fluid shear stress, and actin cytoskeleton tension in stem cell behaviors and differentiation. The review explores mesenchymal stem cell fate decisions, pluripotent stem cells (PSCs), self-renewal, pluripotency, and differentiation to blood products. Understanding how cells sense their microenvironment or niche and mimic those microenvironments in vitro could improve the efficiency of producing stem cell products and the efficacy of the products.
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Hsu, Ping-Chih, David M. Jablons, Cheng-Ta Yang, and Liang You. "Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)." International Journal of Molecular Sciences 20, no. 15 (August 5, 2019): 3821. http://dx.doi.org/10.3390/ijms20153821.
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The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.
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Morciano, Giampaolo, Bianca Vezzani, Sonia Missiroli, Caterina Boncompagni, Paolo Pinton, and Carlotta Giorgi. "An Updated Understanding of the Role of YAP in Driving Oncogenic Responses." Cancers 13, no. 12 (June 21, 2021): 3100. http://dx.doi.org/10.3390/cancers13123100.
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Yes-associated protein (YAP) has emerged as a key component in cancer signaling and is considered a potent oncogene. As such, nuclear YAP participates in complex and only partially understood molecular cascades that are responsible for the oncogenic response by regulating multiple processes, including cell transformation, tumor growth, migration, and metastasis, and by acting as an important mediator of immune and cancer cell interactions. YAP is finely regulated at multiple levels, and its localization in cells in terms of cytoplasm–nucleus shuttling (and vice versa) sheds light on interesting novel anticancer treatment opportunities and putative unconventional functions of the protein when retained in the cytosol. This review aims to summarize and present the state of the art knowledge about the role of YAP in cancer signaling, first focusing on how YAP differs from WW domain-containing transcription regulator 1 (WWTR1, also named as TAZ) and which upstream factors regulate it; then, this review focuses on the role of YAP in different cancer stages and in the crosstalk between immune and cancer cells as well as growing translational strategies derived from its inhibitory and synergistic effects with existing chemo-, immuno- and radiotherapies.
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Shrestha, Madhu, Toshinori Ando, Chanbora Chea, Shinnichi Sakamoto, Takashi Nishisaka, Ikuko Ogawa, Mutsumi Miyauchi, and Takashi Takata. "The transition of tissue inhibitor of metalloproteinases from -4 to -1 induces aggressive behavior and poor patient survival in dedifferentiated liposarcoma via YAP/TAZ activation." Carcinogenesis 40, no. 10 (May 10, 2019): 1288–97. http://dx.doi.org/10.1093/carcin/bgz023.
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AbstractLiposarcoma (LS) is the most common soft-tissue sarcoma. Dedifferentiated liposarcoma (DDLS) shows more aggressive biological behavior than that of well-differentiated liposarcoma (WDLS), so advanced therapeutic agents based on molecular mechanism are urgently needed. Here we show that tissue inhibitors of metalloproteinases (TIMPs) from TIMP-1 to TIMP-4 are differently expressed and regulate yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) in LS. Database analysis showed high TIMP-1 expression in DDLS patients correlating with poor prognosis, but high TIMP-4 expression in WDLS patients with better prognosis. Stable TIMP-1 knockdown inactivated YAP/TAZ and inhibited proliferation, colony formation and migration in DDLS cells, which was rescued by a constitutive active YAP. However, stable overexpression of TIMP-1 showed the opposite in WDLS cells. Stable TIMP-4 knockdown activated YAP/TAZ and promoted proliferation and migration in WDLS cells, which was suppressed by YAP/TAZ inhibitor (verteporfin) or knockdown of YAP/TAZ. Recombinant TIMP-4 showed opposite results in DDLS cells. These results indicate that dedifferentiation in LS shifts the expression of TIMPs from type 4 to type 1, inducing more aggressive behavior and poor prognosis through YAP/TAZ activation, which can be prognostic markers and therapeutic targets for LS patients.
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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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Zhou, Xiaoguang, Peng Zhang, Hu Han, Hongen Lei, and Xiaodong Zhang. "Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes‐associated protein (YAP) pathway." Journal of Cellular Biochemistry 120, no. 4 (November 11, 2018): 6471–81. http://dx.doi.org/10.1002/jcb.27938.
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Ibrahim, Mayar Tarek, Gennady M. Verkhivker, Jyoti Misra, and Peng Tao. "Novel Allosteric Effectors Targeting Human Transcription Factor TEAD." International Journal of Molecular Sciences 24, no. 10 (May 19, 2023): 9009. http://dx.doi.org/10.3390/ijms24109009.
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The Hippo pathway is an evolutionary conserved signaling network involved in several cellular regulatory processes. Dephosphorylation and overexpression of Yes-associated proteins (YAPs) in the Hippo-off state are common in several types of solid tumors. YAP overexpression results in its nuclear translocation and interaction with transcriptional enhanced associate domain 1-4 (TEAD1-4) transcription factors. Covalent and non-covalent inhibitors have been developed to target several interaction sites between TEAD and YAP. The most targeted and effective site for these developed inhibitors is the palmitate-binding pocket in the TEAD1-4 proteins. Screening of a DNA-encoded library against the TEAD central pocket was performed experimentally to identify six new allosteric inhibitors. Inspired by the structure of the TED-347 inhibitor, chemical modification was performed on the original inhibitors by replacing secondary methyl amide with a chloromethyl ketone moiety. Various computational tools, including molecular dynamics, free energy perturbation, and Markov state model analysis, were employed to study the effect of ligand binding on the protein conformational space. Four of the six modified ligands were associated with enhanced allosteric communication between the TEAD4 and YAP1 domains indicated by the relative free energy perturbation to original molecules. Phe229, Thr332, Ile374, and Ile395 residues were revealed to be essential for the effective binding of the inhibitors.
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Kang, Lijing, Juanjuan Yi, Chi-Wai Lau, Lei He, Qinghua Chen, Suowen Xu, Jun Li, et al. "AMPK-Dependent YAP Inhibition Mediates the Protective Effect of Metformin against Obesity-Associated Endothelial Dysfunction and Inflammation." Antioxidants 12, no. 9 (August 28, 2023): 1681. http://dx.doi.org/10.3390/antiox12091681.
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Hyperglycemia is a crucial risk factor for cardiovascular diseases. Chronic inflammation is a central characteristic of obesity, leading to many of its complications. Recent studies have shown that high glucose activates Yes-associated protein 1 (YAP) by suppressing AMPK activity in breast cancer cells. Metformin is a commonly prescribed anti-diabetic drug best known for its AMPK-activating effect. However, the role of YAP in the vasoprotective effect of metformin in diabetic endothelial cell dysfunction is still unknown. The present study aimed to investigate whether YAP activation plays a role in obesity-associated endothelial dysfunction and inflammation and examine whether the vasoprotective effect of metformin is related to YAP inhibition. Reanalysis of the clinical sequencing data revealed YAP signaling, and the YAP target genes CTGF and CYR61 were upregulated in aortic endothelial cells and retinal fibrovascular membranes from diabetic patients. YAP overexpression impaired endothelium-dependent relaxations (EDRs) in isolated mouse aortas and increased the expression of YAP target genes and inflammatory markers in human umbilical vein endothelial cells (HUVECs). High glucose-activated YAP in HUVECs and aortas was accompanied by increased production of oxygen-reactive species. AMPK inhibition was found to induce YAP activation, resulting in increased JNK activity. Metformin activated AMPK and promoted YAP phosphorylation, ultimately improving EDRs and suppressing the JNK activity. Targeting the AMPK–YAP–JNK axis could become a therapeutic strategy for alleviating vascular dysfunction in obesity and diabetes.
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Zhou, Chen, Chunbao Sun, Liya Pi, and Chenglong Li. "Abstract 4513: Exploration degradation of intrinsically disordered protein YAP induced by PROTACs." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4513. http://dx.doi.org/10.1158/1538-7445.am2024-4513.
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Abstract Yes-associated protein (YAP), a potent oncogene and a key player in the Hippo tumor suppression pathway, has long been considered challenging to target due to its partially intrinsically disordered nature. However, recent advancements in High-throughput Screening (HTS) have yielded a breakthrough, as several YAP binders have been identified, igniting new possibilities in the quest to combat YAP-driven malignancies. Building upon this progress, a novel approach utilizing Proteolysis-Targeting Chimera (PROTAC) technology was employed to design and synthesize a series of YAP degraders. Here, our degraders were created by linking NSC682769, a previously reported YAP binder, with either VHL ligand 2 or pomalidomide using various linkers of different lengths and types. Among these degraders, YZ-6 emerges as the most promising, inducing rapid and sustained YAP degradation via promoting its ubiquitination-proteasome-dependent proteolysis. This process effectively suppressed YAP/TEAD-led transcription in both YAP-dependent NCI-H226 and Huh7 cancer cell lines. In addition to its degradation capabilities, YZ-6 also exhibited antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppressed tumor development in the Huh7 xenograft mouse model, accompanied by a remarkable decrease in YAP levels, without adverse effects on the mice. These findings highlight the potential of PROTAC-mediated degradation as a viable strategy for reducing oncogenic YAP levels and attenuating downstream signaling in cancer cells. Moreover, the development of PROTACs based on NSC672869 holds promise for treating YAP-driven malignancies, opening new avenues for cancer therapy. Citation Format: Chen Zhou, Chunbao Sun, Liya Pi, Chenglong Li. Exploration degradation of intrinsically disordered protein YAP induced by PROTACs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4513.
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Sharma, Jyoti, and Pavneesh Madan. "Characterisation of the Hippo signalling pathway during bovine preimplantation embryo development." Reproduction, Fertility and Development 32, no. 4 (2020): 392. http://dx.doi.org/10.1071/rd18320.
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Blastocyst formation is an important milestone during preimplantation embryo development. During murine preimplantation embryogenesis, the Hippo signalling pathway is known to play a significant role in lineage segregation and henceforth the formation of blastocysts. However, the role of this cell signalling pathway during bovine embryogenesis remains unknown. Thus, the aim of the present study was to characterise the Hippo signalling pathway during bovine preimplantation embryo development. mRNA transcripts of Hippo signalling pathway constituents (i.e. crumbs cell polarity complex component 3 (CRB3), mammalian sterile 20-like 1 (MST1), mammalian sterile 20-like 2 (MST2), Yes associated protein 1 (YAP1), transcriptional coactivator with PDZ-binding motif (TAZ)) were observed during all stages of bovine preimplantation embryo development. To evaluate the localisation of Hippo pathway components, bovine embryos at timed stages of development were stained using specific antibodies and observed under a laser confocal microscope. Although MST1/2 proteins were in the cytoplasm during various stages of bovine embryonic development, TAZ and phosphorylated (p-) YAP were detected in the nucleus during the blastocyst stages. Localisation of TAZ and p-YAP proteins was distinct in the bovine compared with mouse model, suggesting that the Hippo signalling pathway is regulated differently in early bovine embryos.
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Mohagheghi, Sina, Zohreh Khajehahmadi, and Heidar Tavilani. "Signaling in Simple Steatosis and Non-alcoholic Steatohepatitis Cirrhosis: TGF-β1, YAP/TAZ, and Hedgehog Pathway Activity." Avicenna Journal of Medical Biochemistry 6, no. 2 (November 27, 2018): 26–30. http://dx.doi.org/10.15171/ajmb.2018.07.
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Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in the liver tissue that is usually associated with metabolic disorders. Traditionally, the disease is regarded as a spectrum of pathological conditions ranging from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with progression to cirrhosis. However, so far, there is no available explanation for the disease progression. Several signaling pathways such as transforming growth factor (TGF)-β, hedgehog (HH), and yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling are attributed to the NAFLD pathogenesis. TGF-β1 pathway component expression aligns with HH pathway ligands expression elevate in NASH cirrhosis while they decrease in SS. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway. Similarly, the TAZ level (but not YAP1) is higher in NASH cirrhosis compared to SS. In addition, these three signaling pathways have little molecular similarity but their changes are totally similar in SS and NASH cirrhosis. The present review discusses the main changes in the expression of TGF-β, HH, and YAP/TAZ pathway components in SS and NASH cirrhosis. It is hoped that these data provide a better understanding of the mechanisms that underlie the pathophysiology of NAFLD.
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Lee, Sangmi, Afruja Ahad, Michele Luu, Sohyun Moon, JoyAnn Caesar, Wellington V. Cardoso, Maria B. Grant, and Brahim Chaqour. "CCN1–Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis." Molecular and Cellular Biology 39, no. 18 (July 1, 2019). http://dx.doi.org/10.1128/mcb.00107-19.
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ABSTRACT Cellular communication network factor 1 (CCN1) is a dynamically expressed, matricellular protein required for vascular development and tissue repair. The CCN1 gene is a presumed target of Yes-associated protein (YAP), a transcriptional coactivator that regulates cell growth and organ size. Herein, we demonstrate that the CCN1 promoter is indeed a direct genomic target of YAP in endothelial cells (ECs) of new blood vessel sprouts and that YAP deficiency in mice downregulates CCN1 and alters cytoskeletal and mitogenic gene expression. Interestingly, CCN1 overexpression in cultured ECs inactivates YAP in a negative feedback and causes its nuclear exclusion. Accordingly, EC-specific deletion of the CCN1 gene in mice mimics a YAP gain-of-function phenotype, characterized by EC hyperproliferation and blood vessel enlargement. CCN1 brings about its effect by providing cells with a soft compliant matrix that creates YAP-repressive cytoskeletal states. Concordantly, pharmacological inhibition of cell stiffness recapitulates the CCN1 deletion vascular phenotype. Furthermore, adeno-associated virus-mediated expression of CCN1 reversed the pathology of YAP hyperactivation and the subsequent aberrant growth of blood vessels in mice with ischemic retinopathy. Our studies unravel a new paradigm of functional interaction between CCN1 and YAP and underscore the significance of their interplay in the pathogenesis of neovascular diseases.
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Sayedyahossein, Samar, Kenneth Huang, Christopher Zhang, Mehdi Karimi, Mehrnoosh Bahmani, Brooke L. O'Donnell, Brent Wakefield, et al. "Pannexin 1 crosstalk with the Hippo pathway in malignant melanoma." FEBS Journal, January 9, 2025. https://doi.org/10.1111/febs.17396.
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In this study, we explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes‐associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, Yes‐associated protein 1 [YAP], Transcriptional coactivator with PDZ‐binding motif [TAZ], and Hippo scaffold, Ras GTPase‐activating‐like protein IQGAP1 [IQGAP1], in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Notably, our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its cotranscriptional activity in melanoma and breast carcinoma cells. Importantly, our study highlights the potential therapeutic significance of targeting PANX1. Pharmacological inhibition of PANX1 using selective FDA‐approved inhibitors or PANX1 knockdown reduced YAP levels in melanoma cells. Furthermore, our Clariom™ S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), β‐galactoside binding protein and galectin‐3 (LGALS3), that are affected in PANX1‐deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment.
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Zhao, Bei, Jun Xie, Xiyuan Zhou, Lixia Zhang, Xiankui Cheng, and Chenglin Liang. "YAP activation in melanoma contributes to anoikis resistance and metastasis." Experimental Biology and Medicine, December 13, 2020, 153537022097710. http://dx.doi.org/10.1177/1535370220977101.
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Melanoma is inherently heterogeneous, providing resistance to apoptosis. Anoikis resistance is a hallmark feature of metastatic melanoma to escape apoptosis when cells lose contact with adjacent cells or extracellular matrix. The yes-associated protein transcription co-activator is the effector of Hippo pathway. Herein, we investigated the function of yes-associated protein in anoikis resistance of melanoma cells. When melanoma cells were grown under anchorage-independent condition, anoikis-resistant cells displayed higher levels of yes-associated protein activation than the cells that were attached to the basement membrane, as evidenced by downregulated phosphorylated yes-associated protein at Ser127 and higher expression of downstream genes BCL2 and MCL-1. Yes-associated protein overexpression directly enhanced the anoikis resistance and metastatic potential of melanoma cells. Conversely, yes-associated protein inhibitor CA3 exhibited Dose-dependent induction of anoikis in resistant melanoma cells and exerted great inhibition on cell migration. Knockdown of yes-associated protein expression by shRNA also rendered melanoma cells susceptible to anoikis and interrupted cell invasiveness. Yes-associated protein inhibition in anoikis-resistant cells also reduced the number of metastatic nodules in the lung sections of SCID mice. Clinically, higher yes-associated protein level in the lung metastasis tissues correlated with higher BCL2 and MCL1 expressions compared with the non-metastasis tissues. Overall, our finding suggests that the aberrant activation of yes-associated protein exerts important role on anoikis resistance and metastatic capability of melanoma cells.