更新于：2024-05-01

STK24

serine/threonine kinase 24

更新于：2024-05-01

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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581

项与 STK24 相关的文献（医药）

2024-02-13·Nitric oxide : biology and chemistry

The role and mechanism of hydrogen sulfide in liver fibrosis.

Review

作者: Shaoyu Mao ; Xuemei Wang ; Miaoqing Li ; Hanshu Liu ; Hongxia Liang

Hydrogen sulfide (H₂S) is the third new gas signaling molecule in the human body after the discovery of NO and CO. Similar to NO, it has the functions of vasodilation, anti-inflammatory, antioxidant, and regulation of cell formation. Enzymes that can produce endogenous H₂S, such as CSE, CSB, and 3-MST, are common in liver tissues and are important regulatory molecules in the liver. In the development of liver fibrosis, H₂S concentration and expression of related enzymes change significantly, which makes it possible to use exogenous gases to treat liver diseases. This review summarizes the role of H₂S in liver fibrosis and its complications induced by NAFLD and CCl₄, and elaborates on the anti-liver fibrosis effect of H₂S through the mechanism of reducing oxidative stress, inhibiting inflammation, regulating autophagy, regulating glucose and lipid metabolism, providing theoretical reference for further research on the treatment of liver fibrosis with H₂S.

2024-02-08·JCI insight

Myofilament-based physiological regulatory compensation preserves diastolic function in failing hearts with severe Ca2+ handling deficits.

Article

作者: Frazer I Heinis ; Brian R Thompson ; Rishi Gulati ; Matthew Wheelwright ; Joseph M Metzger

Severe dysfunction in cardiac muscle intracellular Ca2+ handling is a common pathway underlying heart failure. Here we used an inducible genetic model of severe Ca2+ cycling dysfunction by the targeted temporal gene ablation of the cardiac Ca2+ ATPase, SERCA2, in otherwise normal adult mice. In this model, in vivo heart performance is surprisingly little affected initially, even though Serca2a protein is markedly reduced. The mechanism underlying the sustained in vivo heart performance in the weeks prior to complete heart pump failure and death is not clear and important to understand. Studies were primarily focused on understanding how in vivo diastolic function could be relatively normal under conditions of marked Serca2a deficiency. Interestingly, data show increased cardiac TnI serine 23/24 phosphorylation content in hearts upon Serca2a ablation in vivo. We report that in hearts isolated from the Serca2 deficient mice retained near normal heart pump functional responses to ß-adrenergic stimulation. Unexpectedly, using genetic complementation models, in concert with inducible Serca2 ablation, data show that Serca2a deficient hearts that also lacked the central ß-adrenergic signaling-dependent Serca2a negative regulator, phospholamban (PLN), had severe diastolic dysfunction that could still be corrected by ß-adrenergic stimulation. Notably, integrating a serine 23/24 to alanine PKA-refractory sarcomere incorporated cardiac troponin I molecular switch complex in mice deficient in Serca2 showed blunting of ß-adrenergic stimulation-mediated enhanced diastolic heart performance. Taken together, these data provide new evidence of a compensatory regulatory role of the myofilaments as a critical physiological bridging mechanism to aid in preserving heart diastolic performance in failing hearts with severe Ca2+ handling deficits.

2024-01-19·Diabetes

Excess Salt Intake Activates IL-21-dominant Autoimmune Diabetogenesis via A Saltregulated Ste20-related Proline/alanine-rich Kinase in CD4 T Cells.

Article

作者: Jing-Jie Ciou ; Ming-Wei Chien ; Chao-Yuan Hsu ; Yu-Wen Liu ; Jia-Ling Dong ; Shin-Ying Tsai ; Sung-Sen Yang ; Shih-Hua Lin ; B Lin-Ju Yen ; Shin-Huei Fu ; Huey-Kang Sytwu

The fundamental mechanisms whereby a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Despite excess dietary salt intake acts as a risk factor for autoimmune diseases, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high-salt intake on autoimmune diabetes, non-obese diabetic (NOD) mice were fed with a high-salt diet (HSD) or a normal-salt diet from 6 to 12 weeks of age and monitored for diabetes development. Our results revealed that HSD accelerated diabetes progression with more severe insulitis in NOD mice in a CD4+ T cell-autonomous manner when compared to NSD group. Moreover, expression of IL-21 and SPAK in splenic CD4+ T cells from HSD-fed mice was significantly upregulated. Accordingly, we generated T cell-specific SPAK knockout (CKO) NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK CKO mice when compared to HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T cell pathogenicity. Finally, pharmacological inhibition of SPAK activity using a specific SPAK inhibitor (closantel) in NOD mice ameliorated diabetogenesis, further illuminating the potential of a SPAK-targeting immunotherapeutic approach for autoimmune diabetes. Here, we illustrate that a substantial association between salt sensitivity and the functional impact of SPAK on T cell pathogenicity serves as a central player linking high-salt intake influences to immune-pathophysiology of diabetogenesis in NOD mice.

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