更新于：2024-11-01

STK24

更新于：2024-11-01

基本信息

别名

Mammalian STE20-like protein kinase 3、Mammalian STE20-like protein kinase 3 C-terminal、Mammalian STE20-like protein kinase 3 N-terminal

+ [16]

简介

Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. In association with STK26 negatively regulates Golgi reorientation in polarized cell migration upon RHO activation (PubMed:27807006). Regulates also cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.

关联

项与 STK24 相关的药物

JA-310

靶点

STK24

作用机制

STK24调节剂

在研机构

Johann Wolfgang Goethe-Universität Frankfurt am Main

原研机构

Johann Wolfgang Goethe-Universität Frankfurt am Main

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 STK24 相关的临床结果

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100 项与 STK24 相关的转化医学

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0 项与 STK24 相关的专利（医药）

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582

项与 STK24 相关的文献（医药）

2024-12-01·Biochemical Pharmacology

Increased hydrogen sulfide turnover serves a cytoprotective role during the development of replicative senescence

Article

作者: Szabo, Csaba ; Kieronska-Rudek, Anna ; Chlopicki, Stefan ; Ascencao, Kelly

The mammalian gasotransmitter hydrogen sulfide (H₂S) is produced by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST). Prior studies suggest that H₂S may have cytoprotective and anti-aging effects. This project explores the regulation and role of endogenous H₂S in a murine model of replicative senescence. H₂S and polysulfide levels in RAW 264.7 murine macrophages (control cells: passage 5-10; senescent cells: passage 30-40) were measured using fluorescent probes. The expression of H₂S-related enzymes and the activity of senescence marker beta-galactosidase (SA-β-Gal) were also analyzed. CBS, CSE, and 3-MST were inhibited using selective pharmacological inhibitors. Senescence led to a moderate upregulation of CBS and in a significant increase in CSE and 3-MST. H₂S degradation enzymes were also elevated in senescence. Inhibition of H₂S-producing enzymes reduced H₂S levels but increased polysulfides. Inhibition of H₂S production during senescence suppressed cell proliferation, and elevated SA-β-Gal and p21 levels. Comparing young and old mice spleens revealed downregulation of CBS and ETHE1 and upregulation of rhodanese and SUOX in older mice. The results demonstrate that increased reactive sulfur turnover occurs in senescent macrophages and that reactive sulfur species support cell proliferation and regulate cellular senescence.

2024-10-30·Bioscience Reports

Asynchronous changes of hydrogen sulfide and its generating enzymes in most tissues with the aging process

Article

作者: Bai, Lu ; Miao, Yuxin ; Wu, Yuming ; Liu, Biyu ; Teng, Xu ; He, Kaichuan ; Lu, Ao ; Tan, Bo ; Song, Chengqing ; Chen, Qian ; Dai, Jing

AbstractAging is an inevitable and irreversible biological process that gradually heightens the risks of various diseases and death. As a newly discovered endogenous gasotransmitter, hydrogen sulfide (H2S) has been identified to exert multiple beneficial impacts on the regulation of aging and age-related pathologies. This study was aimed at systematically exploring the relationship between asynchronous aging processes and H2S concentrations in various tissues of aging mice. Samples of plasma and 13 tissues were collected from four cross-sectional age groups (3, 6, 12 and 18 months of age) covering the lifespan of male C57BL/6J mice. The H2S concentration was quantified by a reported liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with monobromobimane derivatization. Additionally, the expressions of cystathionine γ-lyase (CSE), cystathionine β-synthase and 3-mercaptopyruvate sulfurtransferase, in those tissues were analyzed by Western blotting. We discovered that the H2S concentrations decreased asynchronously with the aging process in plasma, heart, liver, kidney, spleen, subcutaneous fat and brown fat and increased in brain and lung. At least one of the three H2S-generating enzymes expressions was compensatorily up-regulated with the aging process in most tissues, among which the up-regulation of CSE was the most prominent.

2024-10-01·Journal of Lipid Research

GCKIII Kinases Control Hepatocellular Lipid Homeostasis via Shared Mode of Action

Article

作者: Asiedu, Bernice ; Andersson, Emma ; Henricsson, Marcus ; Saghaleyni, Rasool ; Blüher, Matthias ; Svensson, L Thomas ; Cansby, Emmelie ; Xia, Ying ; Caputo, Mara ; Hoy, Andrew J ; Svensson, L. Thomas ; Hoy, Andrew J. ; Mahlapuu, Margit

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading global cause of chronic liver disease. Our recent translational investigations have shown that the STE20-type kinases comprising the GCKIII subfamily - MST3, STK25, and MST4 - associate with hepatic lipid droplets and regulate ectopic fat storage in the liver; however, the mode of action of these proteins remains to be resolved. By comparing different combinations of the silencing of MST3, STK25, and/or MST4 in immortalized human hepatocytes, we found that their single knockdown results in a similar reduction in hepatocellular lipid content and metabolic stress, without any additive or synergistic effects observed when all three kinases are simultaneously depleted. A genome-wide yeast two-hybrid screen of the human hepatocyte library identified several interaction partners contributing to the GCKIII-mediated regulation of liver lipid homeostasis, i.e., PDCD10 that protects MST3, STK25, and MST4 from degradation, MAP4K4 that regulates their activity via phosphorylation, and HSD17B11 that controls their action via a conformational change. Finally, using in vitro kinase assays on microfluidic microarrays, we pinpointed various downstream targets that are phosphorylated by the GCKIII kinases, with known functions in lipogenesis, lipolysis, and lipid secretion, as well as glucose uptake, glycolysis, hexosamine synthesis, and ubiquitination. Together, this study demonstrates that the members of the GCKIII kinase subfamily regulate hepatocyte lipid metabolism via common pathways. The results shed new light on the role of MST3, STK25, and MST4, as well as their interactions with PDCD10, MAP4K4, and HSD17B11, in the control of liver lipid homeostasis and MASLD susceptibility.

项与 STK24 相关的新闻（医药）

2024-03-04

·精准药物

新型药物靶标

本文将近期药物研发新兴靶标进行汇总，涵盖肿瘤、代谢、呼吸系统等领域，这些靶标一般是近期报道的具有一定治疗潜力的新型靶标，以期为科研人员提供参考。新型靶标的发现是药物研发的关键。本文就近期在国际知名期刊报道的新型药物靶标的研发进展进行汇总（表1），并参考数据库对不同靶标的候选药物研发进展进行阐述。表1：近期报道的新型药物靶标列举Pin1蛋白的SUMOylation（SUMO化修饰）是近年来备受关注的一类蛋白翻译后修饰，高度的蛋白SUMO化促进了结直肠癌、乳腺癌和脑癌等多种肿瘤发展。近期，在Nature Communications上发表了题为“Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells”的文章（Ref 1），其发现Pin1蛋白在胶质瘤干细胞（GSC）中被去泛素化酶USP34稳定而高表达，且Pin1通过催化已知唯一的SUMO E2酶Ubc9来促进GSC中的全局蛋白SUMO化，并揭示了调控Pin1/USP34、Pin1/Ubc9结合的多个激酶，为靶向Pin1蛋白和全局蛋白SUMO化治疗包括胶质瘤在内的癌症提供了多个潜在药物靶标，具有十分重要的基础与转化意义。在该研究中，使用Pin1抑制剂Sulfopin和CDK1抑制剂RO3306联合治疗荷瘤小鼠，有效抑制了GSC中的SUMO1型蛋白SUMO化修饰，减缓了小鼠颅内胶质母细胞瘤（GBM）的生长，极大延长了小鼠生存期。总之，该研究阐明了肿瘤中调控Pin1蛋白稳定性的上游机制，剖析了Pin1上调SUMO1型蛋白SUMO化的下游机制，有助于发展针对GBM和其它受Pin1驱动的恶性肿瘤的治疗新策略。OTUB2肿瘤免疫逃逸给肿瘤的治疗带来了极大障碍。PD-1/PD-L1通路是肿瘤细胞进行免疫逃逸的关键通路。近期，在Nature Communications上发表了题为“Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1”的文章（Ref 2），确定了肿瘤细胞表达的Otubain-2（OTUB2）是抗肿瘤免疫的负调控因子，通过PD-1/PD-L1信号通路在各种人类癌症中发挥作用，并表明OTUB2具有成为肿瘤诊断和治疗靶标的潜力。在该研究中，通过对TCGA数据分析，发现OTUB2与T细胞活化基因表达呈负相关。随后，通过免疫沉淀质谱等方法，发现了OTUB2和PD-L1存在相互作用，其中PD-L1的ICD结构域以及OTUB2酶活部位的第51位半胱氨酸对OTUB2与PD-L1的相互作用至关重要。在机制方面，OTUB2与PD-L1相互作用，并通过干预内质网蛋白降解（ERAD）通路使PD-L1蛋白去泛素化和稳定。总之，该研究揭示了去泛素化酶OTUB2通过去泛素化作用稳定PD-L1从而促进肿瘤免疫逃逸的机制，并提出了利用靶向OTUB2的功能抑制剂来降低肿瘤细胞PD-L1表达水平，增强细胞毒性T细胞抗肿瘤免疫应答的肿瘤治疗策略。STK24丝氨酸/苏氨酸激酶STK24属于Ste20家族的生发中心激酶（GCK）Ⅲ亚家族，主要涉及激活调控多种细胞功能（包括细胞凋亡和细胞迁移）的丝裂原活化蛋白激酶（MAPK）级联反应。近期，在Advanced Science上发表了题为“Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis”的文章（Ref 3），其揭示了STK24在通过磷酸化AKT和促进PD-L1表达来协调肿瘤免疫逃逸反应中的关键作用，并且通过STK24抑制有效克服了肿瘤对抗PD-1疗法的内在抵抗。研究发现STK24通过削弱肿瘤免疫力来促进肿瘤发生。在免疫缺陷小鼠中，STK24缺陷对肿瘤形成没有明显影响，但在免疫正常的小鼠中显著阻碍肿瘤生长，并伴随着细胞毒性CD8+T细胞和自然杀伤（NK）细胞在肿瘤组织中的增加浸润。进一步发现，STK24通过磷酸化AKT的一个先前未被发现的Thr21位点来增强肿瘤细胞中PD-L1的表达。STK24缺陷显著提高了抗PD-1免疫治疗的疗效。STK24的表达水平与AKT Thr21磷酸化和PD-L1的表达呈正相关，与CD8+T细胞的浸润和患者的生存结果呈负相关。总之，该研究表明STK24可能是开发更有效的免疫治疗干预措施的潜在靶标。PAK4化疗是治疗晚期非小细胞肺癌（NSCLC）的主要方法，使用顺铂的化疗是一线治疗的主要方法。顺铂通过诱导凋亡直接杀死癌细胞，但长期使用顺铂常常导致耐药。p21活化激酶（PAKs）是一个丝氨酸/苏氨酸（Thr）蛋白激酶家族，与许多致癌信号通路密切相关。PAKs在基因转录、细胞骨架重组、致癌转化、细胞增殖和细胞侵袭等方面发挥调控作用。近期，在Cell Death Discovery上发表了题为“Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress”的文章（Ref 4），其揭示PAK4可能是NSCLC化疗耐药性的一个有价值的治疗靶标。研究数据表明，通过抑制GRP78表达，PAK4敲低可通过调节内质网应激来促进NSCLC对顺铂的敏感性。这为顺铂耐药的机制研究提供新见解。【参考资料】1. 科睿唯安CDDI数据库, 检索日期: 2024年1月23日.2. 生物世界、转化医学网、BioArt、医药观澜、iNature、学术经纬等公开网络资源.声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

免疫疗法