更新于：2024-05-01

MST2

serine/threonine kinase 3

更新于：2024-05-01

基本信息

别名

hippo (Drosophila) homolog、KRS1、Mammalian STE20-like protein kinase 2

+ [12]

简介

Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. 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. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.

关联

项与 MST2 相关的药物

XMU-MP-1

靶点

MST2 x STK4

作用机制

MST2调节剂 [+1]

在研机构-

原研机构

厦门大学

在研适应症-

非在研适应症

肝损伤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MST2 相关的临床结果

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100 项与 MST2 相关的转化医学

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0 项与 MST2 相关的专利（医药）

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434

项与 MST2 相关的文献（医药）

2024-02-15·Heliyon

DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis.

Article

作者: HaiFeng Jiang ; WeiChao Su ; HaiXing Wang ; ChunYing Luo ; YaTao Wang ; LinJun Zhang ; LingTao Luo ; ZeBin Lu ; DongYan Shen ; GuoQiang Su

Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.

2024-01-31·Digestive diseases (Basel, Switzerland)

Association study between SNPs in MST1 and MST2 genes and H. pylori infection as well as non-cardia gastric carcinogenesis.

Article

作者: Licong Ma ; Fang Gao ; Wenjie Dong ; Qiang Song ; Yanbin Jia

Introduction Gastric cancer (GC) remains a global health challenge, and H. pylori infection is a main risk factor for non-cardia GC. The present study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in Mammalian sterile 20-like kinase 1 (MST1) and MST2, Helicobacter pylori (H. pylori) infection, and the risk of non-cardia gastric cancer (GC). Methods A case-control study was conducted using enzyme-linked immunosorbent assay (ELISA) and Taqman method to detect the titer of anti-H. pylori antibody in normal human serum and genotype 9 SNPs of MST1 and MST2 genes among 808 samples. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and H. pylori infection, as well as the risk of non-cardia gastric cancer in codominant, dominant, overdominant, recessive, and log-additive genetic models. Haplotypes were constructed using the Haploview 4.2 software. Results The CC genotype of MST2 SNP rs10955176 was associated with a reduced risk of H. pylori infection compared to the TT+CT genotype. None of other SNPs were associated with H. pylori infection. The TT genotype of MST2 SNP rs7827435 was associated with a reduced risk of non-cardia gastric cancer compared to the AA+AT genotype. None of the SNPs were associated with non-cardia gastric cancer. There were no associations between haplotypes and H. pylori infection or the risk of non-cardia gastric cancer. Conclusions The CC genotype of rs10955176 and the TT genotype of rs7827435 may serve as protective factors against H. pylori infection and non-cardia gastric cancer risk, respectively.

2024-01-01·PloS one

AGO2-RIP-Seq reveals miR-34/miR-449 cluster targetome in sinonasal cancers.

Article

作者: Marco Tomasetti ; Federica Monaco ; Corrado Rubini ; Marzia Rossato ; Concetta De Quattro ; Cristina Beltrami ; Giacomo Sollini ; Ernesto Pasquini ; Monica Amati ; Gaia Goteri ; Lory Santarelli ; Massimo Re

Sinonasal tumours are heterogeneous malignancies, presenting different histological features and clinical behaviour. Many studies emphasize the role of specific miRNA in the development and progression of cancer, and their expression profiles could be used as prognostic biomarkers to predict the survival. Recently, using the next-generation sequencing (NGS)-based miRNome analysis the miR-34/miR-449 cluster was identified as miRNA superfamily involved in the pathogenesis of sinonasal cancers (SNCs). In the present study, we established an Argonaute-2 (AGO2): mRNA immunoprecipitation followed by high-throughput sequencing to analyse the regulatory role of miR-34/miR-449 in SNCs. Using this approach, we identified direct target genes (targetome), which were involved in regulation of RNA-DNA metabolic, transcript and epigenetic processes. In particular, the STK3, C9orf78 and STRN3 genes were the direct targets of both miR-34c and miR-449a, and their regulation are predictive of tumour progression. This study provides the first evidence that miR-34/miR-449 and their targets are deregulated in SNCs and could be proposed as valuable prognostic biomarkers.

项与 MST2 相关的新闻（医药）

2023-03-24

·生物谷

南方科技大学王艺瑾团队发表感染及肝脏疾病线粒体稳态系列研究成果

炎症过激活是脓毒症器官损伤发生的决定因素。心肌收缩和松弛是消耗能量的过程，高度依赖线粒体ATP供应。线粒体质量控制(mitochondrial quality control，MQC) 是一种细胞内源性保护程序，用于维持线粒体稳态。该系统调节线粒体分裂/融合，线粒体自噬和生物发生，以修复或去除结构不良的线粒体，从而维持线粒体功能和ATP的产生。增加融合或减少分裂可减少碎片线粒体的形成，同时线粒体自噬有助于消除无法修复的细胞器。尽管在脓毒性心肌病 (SCM) 中观察到线粒体损伤，但相关的MQC功能障碍和调节机制仍不清楚。2023年1月，王艺瑾团队在Metabolism-Clinical and Experimental (中科院一区)发表题为TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury的研究论文。作者构建了心肌细胞特异性TMBIM6敲除小鼠 (TMBIM6CKO) 和TMBIM6转基因小鼠 (TMBIM6TG)，揭示了TMBIM6-VDAC1相互作用可以阻止VDAC1寡聚化，从而维持体内线粒体Ca2+平衡以及正常的MQC过程，有助于改善SCM的心肌功能。本研究揭示了TMBIM6在脓毒症中通过维持[Ca2+]m稳态，从而改善心肌细胞中的线粒体动态平衡，为进一步了解脓毒症相关线粒体功能障碍的分子机制提供了新的见解。预防脓毒症相关TMBIM6下调的策略可能有助于通过保留VDAC1单体构象状态来缓解脓毒症诱导的心肌损伤。文章链接：https://www-sciencedirect-com.libproxy1.nus.edu.sg/science/article/pii/S002604952200261X丝氨酸/苏氨酸激酶3（STK3），也被称为哺乳动物无菌20样激酶1（Mst1），是影响细胞凋亡和氧化应激的Hippo途径的核心成分。STK3的几个底物已被报道，包括GULT1、MAPK、NLRP3、LTB4、SAV1等。以前的研究结果主要阐明了STK3在多种心血管疾病下的病理作用，如糖尿病心肌病、儿茶酚胺诱发的心肌病、以及应激性心肌肥大。然而，STK3在脓毒症心肌病中的作用未见报道。2023年3月，王艺瑾团队在Int J Biol Sci上发表题为Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation的研究论文。作者构建了STK3敲除小鼠 (STK3-/-)，揭示了STK3过度表达通过直接结合KEAP1并诱发其磷酸化，继而干扰KEAP1入核转位并由此下调Nrf2的转录，从而造成线粒体氧化应激损伤，最终扩大脓毒症条件下的心功能障碍。阻止STK3上调、逆转KEAP1磷酸化、增强Nrf2转录的手段和药物，可能是预防或治疗脓毒症心肌病的关键手段。文章链接：https://www.ijbs.com/v19p1369.htm酒精性肝病(ALD)的特征是过量饮酒导致肝组织病变。ALD的唯一有效治疗方法是戒酒，但这对酒精性肝硬化患者的预后没有显著改善。探究酒精性肝损伤分子机制可为ALD的防治提供新的途径。2023年3月，王艺瑾团队在Int J Biol Sci 上发表题为“Interaction between dual specificity phosphatase-1 and cullin-1 attenuates alcohol-related liver disease by restoring p62-mediated mitophagy”的研究论文。本文发现DUSP1下调是ALD发生的初始信号，DUSP1通过抑制线粒体自噬而导致线粒体功能障碍。在生理条件下，DUSP1与胞浆中的CUL1结合，阻止其易位到细胞核。酒精暴露后，DUSP1的表达减少，导致CUL1解离并穿梭到细胞核中，作为转录抑制物抑制Parkin和p62的表达。后者与线粒体自噬受损有关，并损害ATP的生成。通过DUSP1过表达或CUL1缺失来恢复线粒体自噬功能可以极大地减轻ALD肝细胞线粒体功能障碍。文章链接：https://www.ijbs.com/v19p1831.htm肝脏疾病是全球患者死亡的重要原因。线粒体功能障碍与多种急慢性肝病相关。线粒体自噬可以选择性地降解受损线粒体，维持线粒体网络功能的完整性和细胞稳态。在生理状态下，线粒体自噬起到保护肝脏免受组织损伤、维持肝脏稳态的作用。而线粒自噬受损或过激活在肝病发病机制中起重要作用。线粒体自噬介导的线粒体降解途径、线粒体自噬在肝脏疾病中的稳态失衡以及改变线粒体自噬是否可以作为肝脏病治疗靶点已有广泛研究。2023年3月，王艺瑾团队在Antioxidants & Redox Signaling发表题为“The Role and Mechanism of Action of Mitophagy in Various Liver Diseases”的长篇综述，总结了线粒体自噬在各种肝脏疾病中的作用以及以线粒体自噬为靶点的潜在的治疗方案，对肝脏疾病发病机制及治疗具有重要意义。文章链接：https://www-liebertpub-com.libproxy1.nus.edu.sg/doi/epub/10.1089/ars.2022.0114通讯作者简介：王艺瑾南方科技大学医学院副教授，博士生导师深圳市海外高层次人才北京市科技新星计划获得者欧洲肝病学会青年科学奖获得者中国戊型肝炎研究协作组(CCSHE)组长中国研究型医院学会肝病专委会青年委员会副主委以第一/通讯作者在国际学术期刊Lancet RM, Science Advances, Gastroenterology, Hepatology, Journal of Hepatology, Medicine, EBioMedicine发表论文多篇，他引7000余次，入选2022全球前2%顶尖科学家榜单。研究领域：1、肝炎病毒-宿主互作、抗病毒天然免疫机制及策略2、脓毒症发病机制3、线粒体稳态在感染及谢性疾病中的调控机制4、脂肪肝发病机制5、肝脏肿瘤

2023-02-27

·生物谷

Cancer Res: ROR2可能为前列腺癌潜在的生物标志物

前列腺癌症（PCa）是男性癌症相关死亡的主要原因。雄激素剥夺治疗（ADT）仍然是标准的全身治疗，但患者总是进展为转移性去势耐受性前列腺癌症（mCRPC）。前列腺癌症（PCa）是男性癌症相关死亡的主要原因。雄激素剥夺治疗（ADT）仍然是标准的全身治疗，但患者总是进展为转移性去势耐受性前列腺癌症（mCRPC）。这些肿瘤大多会对雄激素信号抑制剂（ASIs）的进一步治疗产生反应，但不可避免地会产生耐药性。雄激素受体（AR）和相互作用途径的改变在许多情况下有助于AR的持续活性和肿瘤生长，而其他肿瘤则独立于AR，其中一部分肿瘤具有神经内分泌特征（神经内分泌前列腺癌，NEPC）。Wnt信号的增加是与mCRPC和ASI抵抗进展相关的机制之一。图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/36622276/ 近日，来自哈佛医学院医学与癌症中心医学部血液肿瘤科的研究者们在Cancer Res. 杂志上发表了题为“WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth”的文章，研究结果表明：通过ROR2的WNT5a信号传导激活Hippo通路，以下调YAP1/TAZ活性并抑制肿瘤生长，将ROR2确定为潜在的生物标志物，以识别可能受益于WNT5a相关药物的患者。 WNT5a的非规范Wnt信号传导具有致癌和肿瘤抑制活性，但介导这些特定效应的下游途径仍有待完全建立。在前列腺癌症器官样培养和异种移植模型的一个子集中，Wnt合成的抑制刺激生长，而WNT5a或WNT5a-模拟肽（Foxy5）显著抑制肿瘤生长。 WNT5a导致YAP1活性的ROR2依赖性降低，这与MST1/2、LATS1、MOB1和YAP1的磷酸化增加相关，表明Hippo通路激活。删除MST1/2取消了WNT5a响应。WNT5a类似地激活表达ROR2的黑色素瘤细胞中的Hippo，而在ROR2阴性细胞中的WNT5a抑制Hippo。这种抑制与在表达ROR2的细胞中未观察到的NF2/Merlin的抑制性磷酸化增加有关。 WNT5a还增加了编码Hippo通路成分（包括MST1和MST2）的mRNA，并与前列腺癌症临床数据集中的这些成分呈正相关。相反，ROR2和WNT5a的表达受到YAP1的刺激，并与临床数据集中YAP1活性的增加相关，显示WNT5a/ROR2负反馈回路调节YAP1活性。 WNT5a/FZD介导的对Hippo的抑制与WNT5a/ROR2介导的Hippo激活的模型。图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/36622276/ 综上所述，这些发现确定Hippo通路激活是介导WNT5a肿瘤抑制作用的机制，并表明ROR2的表达可能是WNT5a模拟药物反应性的预测性生物标志物。（生物谷 Bioon.com）参考文献 Keshan Wang et al. WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth. Cancer Res. 2023 Jan 9;CAN-22-3003.doi: 10.1158/0008-5472.CAN-22-3003.

临床结果信使RNA临床研究

2021-03-26

·BioSpace

Three Biopharma Companies Making Their Nasdaq Debut

Noam Galai/Getty Images This week began with four biopharma companies announcing intentions to become publicly traded companies and it’s ending with three companies making their debut on the Nasdaq. This morning, two of those companies, Ikena Oncology and Design Therapeutics, join Edgewise Therapeutics by trading on the exchange. Design Therapeutics Carlsbad, Calif.-based Design Therapeutics begins trading on the Nasdaq under the ticker symbol DSGN. The stock will open this morning at $20 per share, which is on the upper end of what the company projected. Design said it expects to raise approximately $240 million from the IPO, a little bit higher than the $228 million the company previously anticipated. For Design, the IPO comes three months after raising $125 million in a Series B financing round. Finances from the IPO, as well as the cash from the Series B, will be used to develop treatments for nucleotide repeat expansion disorders, including its lead program in Friedreich ataxia, which is expected to enter clinical development in the first half of 2022. Other disorders the company will target with its GeneTac platform will include myotonic dystrophy type-1, and other indications that have yet to be publicly announced. The company is developing a platform of gene-targeted chimera small molecules for the treatment of serious degenerative disorders caused by inherited nucleotide repeat expansions. Ikena Oncology Ikena Oncology, a company focused on developing cancer therapies targeting key signaling pathways that drive the formation and spread of cancer, begins trading on the Nasdaq at $16 per share. The stick will trade under the ticker symbol “IKNA.” Boston-based Ikena said it expects to raise $125 million from the IPO. In January, the company secured $120 million in a Series B financing round. Funds from the IPO and the Series B will support development of the company’s oncology pipeline. Ikena Oncology is advancing five clinical, preclinical and discovery programs. In January, Ikena announced IK-930, a TEAD inhibitor targeting the Hippo signaling pathway, has entered IND-enabling studies. Ikena plans to IND in the second half of 2021 and to initiate a Phase I clinical trial evaluating single-agent IK-930 in biomarker-enriched patient populations, such as those with Hippo pathway-altered tumors. Other assets in development include a lead optimization-stage KRAS signaling program dubbed IK-175; an AHR antagonist known as IK-412; a kynurenine-degrading enzyme; and IK-007, an EP4 receptor antagonist. Ikena has entered into a global strategic collaboration with Bristol Myers Squibb on the IK-175 and IK-412 programs. Edgewise Therapeutics Boulder, Colo.-based Edgewise Therapeutics will also begin selling its common stock this morning on the Nasdaq under the ticker symbol “EWTX.” The stock will begin trading at $16 per share and are expected to net the company about $176 million from the IPO. Like the other two companies, Edgewise Therapeutics recently conducted a financial raise. In December, Edgewise raised $95 million in a Series C financing round. Funds from that round, as well as the IPO, will be used to advance the company’s muscular dystrophy program, as well as other indications. Edgewise’s lead drug candidate is EDG-5506, an orally administered small molecule designed to address the root cause of dystrophinopathies, in development for the treatment of Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD). EDG-5506 is currently being assessed in a Phase I study. Other biopharma companies will soon make their debut on stock exchanges. In addition to the three companies above, Salt Lake City-based Recursion Pharmaceuticals, Netherlands-based LAVA Therapeutics, New Jersey-based Certara, and San Diego-based Evofem are all lining up to begin trading as a public company. Each of these companies announced their intentions this week.

小分子药物IPO