更新于：2024-09-19

WWTR1

更新于：2024-09-19

基本信息

别名

DKFZp586I1419、TAZ、Transcriptional coactivator with PDZ-binding motif

+ [3]

简介

Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:11118213, PubMed:18227151). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18227151). WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation (PubMed:19010321). In conjunction with YAP1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (PubMed:18568018). Plays a key role in coupling SMADs to the transcriptional machinery such as the mediator complex (PubMed:18568018). Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition (PubMed:18227151, PubMed:18568018).

关联

项与 WWTR1 相关的药物

IAG-933

靶点

TEAD x WWTR1 x YAP1

作用机制

TEAD 抑制剂 [+2]

在研机构

Novartis Pharmaceuticals Corp. [+1]

原研机构

Novartis Pharmaceuticals Corp.

在研适应症

间皮瘤 [+2]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

ETS-003

靶点

TEAD x WWTR1 x YAP1

作用机制

TEAD 抑制剂 [+2]

在研机构

上海奕拓医药科技有限责任公司

原研机构

上海奕拓医药科技有限责任公司

在研适应症

间皮瘤 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 WWTR1 相关的临床试验

CTIS2023-508369-34-00 / Recruiting

- CIAG933A12101

开始日期2021-12-07

申办/合作机构

Novartis Pharma AG

NCT04857372 / Recruiting临床1期

An Open-label, Multi-center, Phase I Study of Oral IAG933 in Adult Patients With Advanced Mesothelioma and Other Solid Tumors

The purpose of this study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors with functional YAP/TAZ fusions and to identify the maximum tolerated dose and/or recommended dose.

开始日期2021-10-21

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 WWTR1 相关的临床结果

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100 项与 WWTR1 相关的转化医学

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0 项与 WWTR1 相关的专利（医药）

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635

项与 WWTR1 相关的文献（医药）

2024-12-31·Annals of Medicine

M2 macrophages promote subconjunctival fibrosis through YAP/TAZ signalling

Article

作者: Li, Jingguo ; Cui, Haohao ; Li, Chengcheng ; Guo, Zhihua ; Cheng, Boyuan ; Geng, Xingchen ; Chu, Dandan ; Wang, Yiwei ; Li, Zhanrong ; Liu, Ruixing

PURPOSETo evaluate the role of M2 macrophages in subconjunctival fibrosis after silicone implantation (SI) and investigate the underlying mechanisms.MATERIALS AND METHODSA model of subconjunctival fibrosis was established by SI surgery in rabbit eyes. M2 distribution and collagen deposition were evaluated by histopathology. The effects of M2 cells on the migration (using wound-scratch assay) and activation (by immunofluorescence and western blotting) of human Tenon's fibroblasts (HTFs) were investigated.RESULTSThere were more M2 macrophages (CD68+/CD206+ cells) occurring in tissue samples around silicone implant at 2 weeks postoperatively. Dense collagen deposition was observed at 8 weeks after SI. In vitro experiment showed M2 expressed high level of CD206 and transforming growth factor-β1 (TGF-β1). The M2-conditioned medium promoted HTFs migration and the synthesis of collagen I and fibronectin. Meanwhile, M2-conditioned medium increased the protein levels of TGF-β1, TGF-βR II, p-Smad2/3, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ). Verteporfin, a YAP inhibitor, suppressedTGF-β1/Smad2/3-YAP/TAZ pathway and attenuated M2-induced extracellular matrix deposition by HTFs.CONCLUSIONSTGF-β1/Smad2/3-YAP/TAZ signalling may be involved in M2-induced fibrotic activities in HTFs. M2 plays a key role in promoting subconjunctival fibrosis and can serve as an attractive target for anti-fibrotic therapeutics.

2024-12-01·Cellular and Molecular Neurobiology

Disease-Associated Neurotoxic Astrocyte Markers in Alzheimer Disease Based on Integrative Single-Nucleus RNA Sequencing

Article

作者: Zhong, Fuxin ; Lü, Yang ; Yu, Wuhan ; Deng, Zhangjing ; Li, Yin ; Wu, Jiani ; Yu, Weihua

AbstractAlzheimer disease (AD) is an irreversible neurodegenerative disease, and astrocytes play a key role in its onset and progression. The aim of this study is to analyze the characteristics of neurotoxic astrocytes and identify novel molecular targets for slowing down the progression of AD. Single-nucleus RNA sequencing (snRNA-seq) data were analyzed from various AD cohorts comprising about 210,654 cells from 53 brain tissue. By integrating snRNA-seq data with bulk RNA-seq data, crucial astrocyte types and genes associated with the prognosis of patients with AD were identified. The expression of neurotoxic astrocyte markers was validated using 5 × FAD and wild-type (WT) mouse models, combined with experiments such as western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence. A group of neurotoxic astrocytes closely related to AD pathology was identified, which were involved in inflammatory responses and pathways related to neuron survival. Combining snRNA and bulk tissue data, ZEP36L, AEBP1, WWTR1, PHYHD1, DST and RASL12 were identified as toxic astrocyte markers closely related to disease severity, significantly elevated in brain tissues of 5 × FAD mice and primary astrocytes treated with Aβ. Among them, WWTR1 was significantly increased in astrocytes of 5 × FAD mice, driving astrocyte inflammatory responses, and has been identified as an important marker of neurotoxic astrocytes. snRNA-seq analysis reveals the biological functions of neurotoxic astrocytes. Six genes related to AD pathology were identified and validated, among which WWTR1 may be a novel marker of neurotoxic astrocytes.

2024-12-01·Cellular and Molecular Life Sciences

Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication

Article

作者: Ibberson, David ; Schmitt, Jennifer ; Poth, Tanja ; Pedrini, Fabiola ; Bissinger, Michaela ; Guo, Te ; Schirmacher, Peter ; Tóth, Marcell ; Marhenke, Silke ; Colucci, Silvia ; Cheng, Wenxiang ; Breuhahn, Kai ; Vogel, Arndt ; Longerich, Thomas ; Birner, Patrizia ; Liu, Kaijing ; Damle-Vartak, Amruta ; Weiler, Sofia M E ; Angel, Peter ; Muckenthaler, Martina U ; Dropmann, Anne ; Pinna, Federico ; Wan, Shan ; Wehling, Lilija ; Rose, Fabian ; Lam, Macrina ; Ali, Adnan ; Heikenwälder, Mathias ; Dooley, Steven

AbstractIntroductionThe Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell–cell communication of non-malignant liver cells.Materials and MethodsTo investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum.ResultsThe loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors.ConclusionYAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell–cell communication originating from NPCs.

项与 WWTR1 相关的新闻（医药）

2024-02-14

·PRNewswire

Beactica Therapeutics' TEAD programme selected for late-breaking research presentation at the AACR Annual Meeting 2024

STOCKHOLM, Feb. 14, 2024 /PRNewswire/ -- Beactica Therapeutics AB, the Swedish precision oncology company, today announced that its TEAD programme has been selected for a late-breaking presentation at the American Association for Cancer Research's Annual Meeting 2024. The conference will take place on April 5-10, 2024 in San Diego, California. Dr Peter Brandt, Head of Chemistry, will present a poster entitled Degraders of TEAD transcription factors based on interface 3 binders on Sunday April 7, 2024, at 1:30 PM – 5:00 PM. The location is at the San Diego Convention Center, Section 52, abstract presentation number: LB029. The session title is Late-Breaking Research: Chemistry. The presentation will include new positive results from studies with novel proteolysis-targeting degraders of TEAD based on interface 3-binding ligands under development by Beactica. This will include head-to-head in vitro comparisons with other classes of TEAD modulators in clinical development such as palmitoylation inhibitors and direct YAP–TEAD protein–protein interaction inhibitors. The work to be presented contains contributions by Beactica's collaborators at the National Center for Advancing Translational Sciences (NCATS), one of 27 institutes and centers at the U.S. National Institutes of Health (NIH). Organised by the American Association for Cancer Research, the AACR Annual Meeting is the largest and most important cancer drug discovery event in the world. It has an anticipated attendance of more than 20 000 scientists, clinicians, advocates, and other attendees. The event spans integrative cancer science, global impact, individualised patient care and showcases the best and most up-to-date cancer science available. About TEAD TEAD 1–4 (Transcriptional Enhanced Associate Domain) are transcription factors that together with its coactivators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) play key roles in the Hippo signalling pathway that regulates cell proliferation, apoptosis, and stemness. Dysregulation of the Hippo pathway and subsequent activation of TEAD has been reported in a wide range of cancers such as squamous cell carcinoma, head and neck, gynaecological, and gastrointestinal cancers. The first clinical proof-of-concept for drugging the Hippo–YAP–TEAD pathway was achieved with the TEAD inhibitor VT3989 and was presented at the American Association for Cancer Research (AACR) Annual Meeting in April 2023. About Beactica Therapeutics Beactica Therapeutics AB is a privately held precision oncology company committed to the fight against cancer. The company is advancing a pipeline of novel small molecule therapeutics with a focus to treat genetically defined cancers with significant unmet medical need. Beactica's approach is centered around targeting synthetically lethal disease proteins with allosteric modulators and targeted protein degraders. Beactica deliver value to patients and shareholders by advancing its programmes to clinical proof of concept. For more information, please visit . Beactica Therapeutics Contact Per Källblad M.Sc. Ph.D. CEO [email protected] Tel: +46 18 56 08 80 The following files are available for download: SOURCE Beactica Therapeutics AB

AACR会议

2023-05-09

·生物制品圈

最新！南加州大学发现肝癌治疗新靶点！

导读：肝细胞癌(HCC)是最致命的第三大恶性肿瘤。肝癌中激活的肝星状细胞(aHSC)与癌症相关的成纤维细胞被认为是一个潜在的治疗靶点。5月8日，南加州大学研究人员在《Nature：Communications》上发表了名为“Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis”的文章，研究人员称发现了新的肝癌治疗靶点。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-38406-8研究背景 01 肝细胞癌(HCC)是第三大最致命的恶性肿瘤。肝细胞癌中激活的肝星状细胞(aHSC)在与癌症相关的成纤维细胞，被认为是一个潜在的治疗靶点。研究人员报道了Scd2（一种饱和酶）在肝星状细胞中抑制肿瘤和肿瘤微环境，并防止雄性小鼠患上肝脏肿瘤。细活化的肝星状细胞(aHSC)促进HCC成为癌症相关成纤维细胞(CAF)。代谢性肝病（如酒精性和非酒精性脂肪性肝炎）目前被认为是肝细胞癌的主要易感因素，取代了病毒性肝炎。然而，在这种情况下，aHSC-HCC串扰在HCC发展中的具体性质尚不清楚。研究方法 02研究人员首先验证了小鼠在肝星状细胞中选择性消融Scd2的作用。为此他们对小鼠肝细胞进行了单细胞RNA测序(scRNA-seq)。该分析确定了表达其标记基因的不同细胞类型的簇。其中，Scd2在内皮细胞、巨噬细胞、门静脉成纤维细胞(PF)、树突状细胞中表达。接下来，我们通过对肝肿瘤邻近组织的RNA测序探讨了aHSC、SCD2缺乏抗肿瘤作用的机制。研究人员认为这些被称为肿瘤邻近肝(TAL)的组织是研究肝星状细胞-肿瘤细胞串扰的理想组织，因为它们在显微镜下，尽管肿瘤并不明显。差异表达基因(DEGs)的热图描绘了不同转录组学景观(图1a)。Yap1的转录受到CTNNB112的正调控，Yap1和CTNNB1同时受到抑制，表示Yap1的抑制可能是由CTNNB1的减少引起的。研究人员还想知道这种调节是肝脏肿瘤发生所特有的，还是也与正常肝脏有关。为此分析了小鼠肝脏中主要在肝细胞和胆管细胞中缺乏CTNNB1的YAP1和Scd1/2的表达。IB分析显示肝脏中YAP1、TAZ、HuR和LRP6下调。CTNNB113和Yap1/ Wwtr1 mRNA的预期靶点Scd1/2也受到抑制。这表明即使在正常肝细胞中，CTNNB1也能正向调节Yap1/ TAZ和SCD-HuR-LRP6通路。SCD2是产生mufa所必需的酶，mufa通过延伸和去饱和产生多不饱和脂肪酸(PUFA)。因此，研究人员对Scd2f/f CC与Scd2f/f肝脏中的PUFA代谢物进行了脂质组学分析。为验证LTB4R2在HCC中的作用，研究人员检测了LTB4R2的药理学和遗传学抑制对人HCC细胞株Huh7生长的影响。LTB4R2拮抗剂LY255283的浓度抑制Huh7的生长。shRNA对LTB4R2的表达使其减少80%，但对LTB4R1 mRNA没有影响，证实了LTB4R2的促生长作用。LTB4R2 KD降低了nYAP1和CTNNB1。LTB4R2在2000年被发现为LTB4的低亲和力受体，随后12-HHTrE被鉴定为高亲和力LTB4R2配体。研究描述了LTB4R2通过激活CTNNB1和YAP1在肝脏肿瘤发展中的作用，CTNNB1和YAP1是两种促进肝脏肿瘤发生的转录激活因子。研究人员的scRNA-seq分析发现，Lrat+Fbln2+ aHSC亚群是CYP1B1催化的12-HHTrE生成的假定来源。scd2依赖性Cyp1b1上调的机制目前尚不清楚，但可能涉及CTNNB1-AhR对Cyp1a134的转录激活。TCGA-LIHC队列分析未能显示LTB4R2表达与不良生存率之间的正相关。研究人员发现的LTB4R2通路可能仅在肝癌生长的病灶区域有活性，并且可能无法通过RNA-seq准确评估。事实上对小鼠的RNA-seq分析未能检测到Ltb4r2表达降低，尽管IB或qPCR显著减少。TME中表达cyp1b1的aHSC群体相对较少。因此，只有那些被CYP1B1+ aHSC包围的HCC细胞才能表达LTB4R2——这是CYPB1-LTB4R2通路独特的局灶性和空间性。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-38406-8研究意义 03肝星状细胞（aHSC）依赖于SCD和CYP1B1的方式释放12-HHTrE，其条件培养基在HCC细胞中再现了ltb4r2介导的12-HHTrE促进肿瘤生长的作用。总之，研究结果表明肝星状细胞启动的12-hhtrer-ltb4r2-ctnnb1-yap1通路是潜在的肝细胞癌治疗靶点。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-38406-8

AHA会议临床结果信使RNA

2022-09-06

·生物制品圈

转录调节因子TAZ：保护衰老细胞免疫功能

导读：免疫系统的特定功能保护我们免受病毒和细菌等病原体引起的感染的影响。然而，随着年龄的增长，免疫系统功能就会下降，这在很大程度上归因于造血干细胞（HSC）中与年龄相关的缺陷，即免疫细胞层次结构的顶点细胞。研究人员发现Hippo信号通路转录效应因子TAZ能在旧的HSC中被有效诱导，并保护这些细胞免受功能下降的影响。研究人员在连接PU.1和Hippo途径共激活剂TAZ的oHSCs中发现了一条途径。了解其在HSCs衰老中的失调可能有助于开发干预治疗策略，从而改善老年人群的免疫功能。该研究发布于《Nature Communications》。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-022-32970-1造血干细胞功能逐渐丧失 01 在自然衰老过程中，造血干细胞（HSC）的功能会逐渐丧失，同时再生潜力降低。关于老年人的另一个显著特征是产生淋巴细胞的数量减少，这可能导致老年人预防感染的能力受损。有充分的证据表明，这些缺陷在很大程度上是由于造血干细胞和祖细胞（HSPC）室的缺陷。矛盾的是，衰老导致免疫表型HSC数量增加，这些HSCs表现出髓系偏倚。多种细胞固有缺陷导致旧HSC的适应性较差，例如极性改变，自噬减少或表观基因组改变。YAP / TAZ 02YAP/TAZ-TEADs通过控制时间和空间特异性靶基因的表达，调控细胞增殖和凋亡来控制器官大小。是一条抑制细胞生长的信号通路，例如在骨细胞分化，脂肪细胞分化，肌细胞分化中都起到一定得调控作用，此外，Hippo信号传导通路不仅在癌症发生和转移、组织再生以及干细胞的功能调控上发挥着重要的作用，同时也受到分子生物学领域的关注。当Hippo信号传导通路被关闭时，YAP / TAZ可以进入细胞核并诱导基因转录。在癌症等病理条件下，YAP / TAZ活性也会发生改变。研究表明它们对于诱导各种组织（例如肠道或肝脏）的再生至关重要。YAP / TAZ可以将细胞离体以及将体内重新编程为更原始的状态，这可能使它们能够更好地应对组织损伤过程中的压力。在稳态条件下，Yap1 或 Wwtr1（编码 TAZ 的基因）的缺失通常会导致表型较弱或无表型，类似于在年轻的 HSC （yHSC）中删除它们，然而，当细胞面临分子损伤时，迫切需要YAP / TAZ来诱导再生反应。TAZ调节免疫功能 03 鉴于它们在再生中的起到的显著作用，研究人员试图研究YAP / TAZ是否需要应对衰老的HSC中的细胞压力和再生潜力的下降。在这里，研究表明Hippo途径共激活剂TAZ在旧的HSC中是能够高度诱导的，并且对于维持这些细胞一定水平的功能至关重要。TAZ诱导的基因Clca3a1是体内TAZ活性的代理，可用于从老年小鼠中分离出“年轻”的HSCs。此外，研究还提供证据表明，TAZ可作为造血转录因子PU.1的共激活剂，以抵消旧HSC中与年龄相关的PU.1活性丧失。这项工作揭示了TAZ在故障安全机制中的重要且未被描述的作用，该机制在机体老化过程中保留了HSC功能。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-022-32970-1