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更新于：2025-05-07

STK39

更新于：2025-05-07

基本信息

别名

DCHT、serine threonine kinase 39、serine/threonine kinase 39

+ [6]

简介

Effector serine/threonine-protein kinase component of the WNK-SPAK/OSR1 kinase cascade, which is involved in various processes, such as ion transport, response to hypertonic stress and blood pressure (PubMed:16669787, PubMed:18270262, PubMed:21321328, PubMed:34289367). Specifically recognizes and binds proteins with a RFXV motif (PubMed:16669787, PubMed:21321328). Acts downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4): following activation by WNK kinases, catalyzes phosphorylation of ion cotransporters, such as SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity (PubMed:21321328). Mediates regulatory volume increase in response to hyperosmotic stress by catalyzing phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1 and SLC12A6/KCC3 downstream of WNK1 and WNK3 kinases (PubMed:12740379, PubMed:16669787, PubMed:21321328). Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux (PubMed:16669787, PubMed:19665974, PubMed:21321328). Acts as a regulator of NaCl reabsorption in the distal nephron by mediating phosphorylation and activation of the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney downstream of WNK4 (PubMed:18270262). Mediates the inhibition of SLC4A4, SLC26A6 as well as CFTR activities (By similarity). Phosphorylates RELT (By similarity).

关联

项与 STK39 相关的药物

closantel

氯生太尔

靶点

OSR1 x STK39

作用机制

OSR1 inhibitors [+1]

在研机构

University of Birmingham

原研机构

University of Birmingham

在研适应症

高血压

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

Rafoxanide

靶点

OSR1 x STK39

作用机制

OSR1 inhibitors [+1]

在研机构

University of Birmingham

原研机构

University of Birmingham

在研适应症

高血压

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

US20230227439

专利挖掘

靶点

STK39

作用机制

STK39抑制剂

在研机构

Yale University

原研机构

Yale University

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 STK39 相关的临床结果

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100 项与 STK39 相关的转化医学

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0 项与 STK39 相关的专利（医药）

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592

项与 STK39 相关的文献（医药）

2025-04-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Development and validation of a kinase-related gene signature as a novel diagnostic and prognostic model for prostate cancer

Article

作者: Wang, Qi ; Wei, Weiyang ; Zhu, Haiying ; Huang, Yaqiang ; Liang, Yingke ; Zhong, Weide ; Liang, Zhenguo ; Mo, Rujun ; Huang, Hongxing ; He, Huichan ; Ye, Jianheng ; Dai, Qishan ; Yang, Hao

BACKGROUNDProstate cancer (PCa) is a prevalent malignant tumor in men worldwide. Kinases play a key role in the development of multiple tumors. Nevertheless, the role of kinases in PCa remains largely unclear.METHODSA kinase-related gene signature was constructed by LASSO Cox regression analysis using the TCGA_PRAD cohort. The diagnostic and prognostic values of the signature were then evaulated. Furthermore, a loss-of-function assay was carried out to explore the function of NEK5 in PCa.RESULTSA signature of 13 kinase-related genes (NEK5, FRK, STK39, STYK1, IGF1R, RPS6KC1, TTK, CDK1, NEK2, PTK6, DAPK1, MELK and EPHA10) was constructed. The PCa patients presenting a high-risk score according to the signature demonstrated poorer disease-free survival compared to those with a low score. Additionally, TMB was found to be remarkably increased in patients categorized as high-risk relative to low-risk patients. Moreover, the 13-gene signature may also have good predictive value for PCa diagnosis. Furthermore, NEK5 expression was remarkably elevated in PCa tissues relative to benign tissues. NEK5 deficiency significantly inhibited PCa cell growth and suppressed mitochondrial OXPHOS.CONCLUSIONThe 13-gene signature constructed in this study may exhibit good performance in PCa diagnosis and prognosis evaluation. We identified the oncogenic role of NEK5 in PCa. NEK5 may serve as a therapeutic target for treatting PCa.

2025-03-01·Nephrology

Plasma Potassium Negatively Correlates With Sodium Chloride Cotransporter Abundance and Phosphorylation in Urinary Extracellular Vesicles From Patients With Chronic Kidney Disease

Article

作者: Stowasser, Michael ; Wu, Aihua ; Fenton, Robert A. ; Vesey, David ; Wolley, Martin J. ; Welling, Paul A. ; Terker, Andrew S.

ABSTRACTAimUsing urinary extracellular vesicles (uEVs), we have demonstrated the functional ‘renal‐K switch’ mechanism (the WNK‐SPAK‐NCC pathway) in both healthy subjects and those with primary aldosteronism. The close relationship between blood pressure and CKD has led to the hypothesis that high potassium intake may be reno‐protective through the same mechanism. This study used uEVs to evaluate whether plasma potassium negatively correlates with NCC and its phosphorylation (pNCC) in patients with CKD.MethodsMorning blood and second morning urine were collected on a single occasion between 8 and 11 AM from patients with various CKD stages. Plasma potassium levels were assessed by a local pathology laboratory. uEVs were obtained by progressive ultracentrifugation, and NCC and pNCC were analysed by western blotting.ResultsCorrelation analyses among 23 patients with CKD revealed the abundance of NCC (R2 = 0.46, p = 0.0003) and pNCC (R2 = 0.30, p = 0.0067) strongly and negatively correlate with plasma potassium. The negative correlations persist among 18 patients who did not receive SGLT2 inhibitors or K‐binders (NCC: R2 = 0.5, p = 0.002; pNCC: R2 = 0.30, p = 0.03) and the negative trends remain among 5 patients who received either SGLT2 inhibitors or K‐binders (NCC: R2 = 0.64, p = 0.11; pNCC: R2 = 0.42, p = 0.24).ConclusionIn patients with CKD, there are negative correlations between NCC and pNCC in uEVs and plasma potassium, which appear independent of eGFR. This suggests that the mechanism at play is distinct from the overall kidney function, and potassium supplement within a safe level may assist in natriuresis and improve cardiovascular outcomes.

2025-03-01·European Journal of Pharmacology

Camk2n1 deficiency reduces the NaCl cotransporter activity through the CUL3/KLHL3/WNK4 complex in the kidney

Article

作者: Zhang, Zihao ; Zhang, Chong ; Zhang, Ya ; Jiang, Gengru

Calcium/calmodulin dependent protein kinase II inhibitor 1 (Camk2n1) is closely associated with a peak logarithm of odds score in quantitative trait loci for systolic blood pressure. Increased Camk2n1 mRNA expression has been specifically observed in the kidneys of hypertension mouse models. However, the precise role of Camk2n1 in the kidney remains unclear. We generated Camk2n1-/- mice using the CRISPR/Cas9 system. Compared to controls, Camk2n1-/- mice exhibited consistently lower systolic blood pressure across all measured time points. Deletion of Camk2n1 resulted in decreased apical labeling of phosphorylated and total thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule. NCC phosphorylation is regulated by activated SPAK/OSR1 kinases, which act downstream of With-No-lysine (K) kinase (WNK). In Camk2n1-/- mice, the elevated abundances of key components of the Cullin 3 (CUL3) RING ubiquitin ligase, including neddylated CUL3 and the adaptor Kelch-like protein 3, promoted proteasomal degradation of WNK4. In renal tissues, Camk2n1 deletion led to increased mRNA and protein levels of ubiquitin-like modifier-activating enzyme 3 (UBA3) and ubiquitin-conjugating enzyme E2 (UBE2M). Conversely, Camk2n1 overexpression in HEK293 cells resulted in decreased levels of UBA3 and UBE2M, along with reduced CUL3 neddylation. Treatment with MLN4924 effectively suppressed CUL3 hyperneddylation and restored WNK4 levels in the kidneys of Camk2n1-/- mice. In summary, Camk2n1 deletion lowers blood pressure, likely by promoting WNK4 degradation through dysregulated CUL3 RING ubiquitin ligase activity, which leads to decreased NCC activity.

项与 STK39 相关的新闻（医药）

2024-12-18

·国际糖尿病idiabetes

WNK1如何作为渗透压感受器发挥作用？——机制及结构-功能研究

ASN微专辑扫描二维码可查看更多内容编者按在2024年美国肾脏病学会（ASN）年会—美国肾脏周（Kidney Week 2024）上，来自美国爱荷华大学医疗保健中心的研究团队报告了一项关于WNK1作为渗透压感受器发挥作用的机制及结构-功能研究成果（TH-OR61）。该研究深入探讨了WNK1如何通过特定机制激活Kv3.1通道进而调节抗利尿激素（AVP）的释放，以及C-端内在无序区（IDR）在此过程中的作用。美国爱荷华大学医疗保健中心Xin Jin分享研究成果脑室周围器（CVO）缺乏完整血脑屏障的结构。CVO神经元能够检测到血清的高渗状态，从而刺激精氨酸加压素（AVP）的产生和释放。Chou-Long Huang等最近报道，CVO神经元中的WNK1能够感知高渗状态并激活Kv3.1通道，增加动作电位，进而增加AVP的释放。Boyd-Shiwarski等人则报道，WNK1在细胞脱水过程中会形成凝聚物（condensates），并激活NKCC1以恢复细胞体积。C端内在无序区（Intrinsically disordered region, IDR）对于凝聚物的形成至关重要。本研究旨在探讨OSR1/SPAK在WNK1激活Kv3.1中的作用，以及IDR在这一激活过程中的作用。研究团队通过立体定向注射携带Cre重组酶的AAV病毒至Spak-null和Osr1-floxed小鼠的CVO区域，构建了CVO中SPAK和OSR1基因敲除小鼠模型。随后，通过代谢笼研究评估了这些小鼠的水稳态，并测定AVP水平。同时，在表达了重组WNK1（或其突变体）、SPAK和Kv3.1的HEK细胞中研究Kv3.1电流的变化。此外，还通过Western blot检测了WNK1的生物化学激酶活性。研究发现高渗环境可使小鼠CVO中p-OSR1/SPAK的水平升高。CVO中OSR1/SPAK缺失的小鼠表现出多尿和尿渗透压降低的症状，即使在限水状态下也持续存在，表明出现了尿崩症。与对照组相比，限水的OSR/SPAK缺失小鼠的循环AVP和copeptin水平较低。在采用全细胞记录方法且电极内液（即细胞内液）含有20 mM氯化物的情况下，将表达全长WNK1、SPAK和Kv3.1的HEK细胞暴露于生理性细胞外高渗溶液（含5 mM氯化钠，简称“HTS”）中，观察到Kv3.1电流增加。当电极内液（即细胞内液）中的氯离子浓度增加到100 mM时，HTS对Kv3.1的激活作用被减弱。重要的是，仅表达WNK1激酶域（氨基酸1-491）、SPAK和Kv3.1的细胞也能对HTS产生反应。此外，HTS还诱导了WNK1（1-491）的自磷酸化。研究得出结论，CVO神经元中的WNK1介导的渗透压感受涉及通过SPAK/OSR1激活Kv3.1。WNK1激酶域可以独立于其C端IDR区域检测细胞外高渗状态。这些结果支持了结构数据，即WNK激酶域空腔内的水和氯离子对激酶活性具有负调控作用。IDR如何与激酶域协调以调节下游效应分子，有待未来研究揭示。结语本研究深化了我们对WNK1作为渗透压感受器在体液平衡调节中作用的理解，还为未来探索渗透压感受机制及其相关疾病的治疗提供了新的视角和思路。期待未来能有更多研究揭示WNK1及其相关分子的复杂调控网络，为临床治疗和药物研发提供理论依据。声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！（来源：《肾医线》编辑部）

2024-12-02

·生物谷

Nature子刊：我国科学家发现了14个与神经质相关的基因

在分析数据中，有14个基因与神经质（neuroticism）有关，其中12个基因以前从未被发现过。神经质（neuroticism）是成熟的心理学理论所描述的一种关键人格特质，与情绪不稳定和消极情绪倾向有关。过去的研究发现，这种人格特质往往与各种精神疾病以及一些慢性重症并存。技术的进步为研究导致疾病和精神障碍的遗传因素提供了新的可能性。类似的方法也可能有助于揭示哪些基因会增加一个人表现出特定人格特质（包括神经质）的概率。过去的研究揭示了人类基因组中与神经质有关的 100 多个位点。然而，关于这种人格特质的可遗传性还有很多有待发现。在一项的研究中，来自中国复旦大学的研究人员通过分析英国生物库（UK Biobank）的数据，开始进一步研究神经质的遗传基础。他们指出，在他们分析的数据中，有14个基因与神经质有关，其中12个基因以前从未被发现过。相关研究结果于2024年11月7日在线发表在Nature Human Behavior期刊上，论文标题为“Large-scale exome sequencing identified 18 novel genes for neuroticism in 394,005 UK-based individuals”。这些作者写道，“现有的神经质基因研究主要局限于常见变异。我们对英国生物库中的英国白人进行了大规模外显子组分析，揭示了编码变异在神经质中的作用。对于罕见变异，崩溃分析（collapsing analysis, 一种通过将基因变异归类为功能组来识别稀有变异的方法）发现了14个神经质相关基因。其中，12个（PTPRE、BCL10、TRIM32、ANKRD12、ADGRB2、MON2、HIF1A、ITGB2、STK39、CAPNS2、OGFOD1和KDM4B）是新发现的，其余的（MADD和TRPC4AP）显示出与常见变异的趋同证据。” 英国生物库提供了一个庞大的数据池，全世界的科学家们都可以对其进行分析，以探索不同基因、生活方式选择和健康疾病之间的相互作用。作为研究的一部分，复旦大学的Xin-Rui Wu、Ze-Yu Li和他们的同事们分析了英国生物库中的454787个外显子组测序数据，以确定与神经质有关的基因。他们的分析揭示了12个与这种人格特质相关的新基因，同时证实了之前研究中已经发现的2个基因与神经质相关。所有13种神经质表型的负荷遗传相关性这些作者写道，“据估计，神经质的罕见编码变异的遗传率高达7.3%。对于常见变异，我们发现了 78 个显著关联，其中涉及 6 个未报告的基因。随后，我们利用对英国生物库中其他四个血统的荟萃分析和 23andMe 样本的汇总数据，重现了这些变异。此外，这些变异对神经精神疾病、认知能力和大脑结构有着广泛的影响。” 他们的研究结果有助于目前对神经质及其遗传基础的理解。未来，这些发现可能会激发新的聚焦于神经质或其他人格特质的基因研究。最终，这些研究工作可能为开发与特定人格特质相关的神经精神疾病的诊断和治疗工具提供信息。这些作者写道，“我们的发现加深了对神经质遗传结构的理解，并为未来的机理研究提供了潜在的靶标。”（生物谷Bioon.com）参考资料： Xin-Rui Wu et al. Large-scale exome sequencing identified 18 novel genes for neuroticism in 394,005 UK-based individuals. Nature Human Behaviour, 2024, doi:10.1038/s41562-024-02045-w. Large-scale genetic study identifies 14 genes linked to neuroticismhttps://medicalxpress.com/news/2024-11-large-scale-genetic-genes-linked.html

基因疗法临床结果