更新于：2024-11-01

LIMK1

更新于：2024-11-01

基本信息

别名

LIM domain kinase 1、LIMK、LIMK-1

+ [1]

简介

Has a dominant negative effect on actin cytoskeletal changes. Required for atypical chemokine receptor ACKR2-induced phosphorylation of cofilin (CFL1). Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11832213, PubMed:12807904, PubMed:15660133, PubMed:16230460, PubMed:18028908, PubMed:22328514, PubMed:23633677). Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop (PubMed:10436159). LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly (PubMed:18028908). Stimulates axonal outgrowth and may be involved in brain development (PubMed:18028908).

关联

项与 LIMK1 相关的药物

TH-257

靶点

LIMK1 x LIMK2

作用机制

LIMK1抑制剂 [+1]

在研机构

University of Cardiff

原研机构

University of Cardiff

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

LIJTF-500025

靶点

LIMK1 x LIMK2

作用机制

LIMK1抑制剂 [+1]

在研机构

University of Cardiff

原研机构

University of Cardiff

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

LIMKi-3

靶点

LIMK1 x LIMK2

作用机制

LIMK1抑制剂 [+1]

在研机构

University of Cardiff

原研机构

University of Cardiff

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 LIMK1 相关的临床结果

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100 项与 LIMK1 相关的转化医学

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0 项与 LIMK1 相关的专利（医药）

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623

项与 LIMK1 相关的文献（医药）

2025-01-01·Experimental Neurology

DDAH1 deficiency exacerbates cerebral vascular endothelial dysfunction by aggravating BBB disruption and oxidative stress in thoracic blast-induced brain injury

Article

作者: Mao, Shun ; Tong, Changci ; Hou, Mingxiao ; Cong, Peifang ; Liu, Yunen ; Shi, Lin

As terrorist incidents and underground explosion events have become more frequent around the world, brain injury caused by thoracic blast exposure has been more highlighted due to its injured organ, subsequent social and economic burden. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in thoracic blast-induced brain injury remains to be explained. This study seeks to investigate the mechanism of DDAH1 on thoracic blast-induced brain injury. 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly and equally divided into control group and blast group, respectively. The integrity of blood-brain barrier (BBB) was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and asymmetric dimethylarginine (ADMA) levels were determined through ELISA. HE staining and reactive oxygen species (ROS) detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, tight junction, focal adhesion, vascular endothelial injury, and the DDAH1/ADMA/eNOS signaling pathway. DDAH1 deficiency aggravated thoracic blast-induced BBB leakage, inflammatory response, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA and IRE-α expression. Regarding cerebral vascular endothelial dysfunction, DDAH1 deficiency increased the expression of MCAM, FN1, LIMK1, VEGF, MMP9, Vimentin and N-cadherin, while lowering the expression of FMR1, Occludin, claudin-3, claudin-5, Lyn, LIMA1, Glrb, Sez6, Dystrophin, and phosphorylation of VASP. Also, DDAH1 deficiency exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Thus, we conclude that DDAH1 could prevent cerebral vascular endothelial dysfunction and related injury by inhibiting ADMA signaling and increasing eNOS activity in thoracic blast induced brain injury.

2024-12-01·Neurobiology of Aging

Age-dependent sex differences in cofilin1 pathway (LIMK1/SSH1) and its association with AD biomarkers after chronic systemic inflammation in mice

Article

作者: Shah, Zahoor A ; Alsegiani, Amsha S. ; Shah, Zahoor A. ; Alsegiani, Amsha S

Chronic systemic inflammation (CSI) results in neuroinflammation and neurodegeneration. Cofilin1 is a stress protein that activates microglia and induces neuroinflammation, but its role in CSI at different aging stages remains unidentified. Therefore, the study aims to identify cofilin1 and its upstream regulators LIMK1 and SSH1 after CSI in young-, middle-, and advanced-aged mice. CSI was induced by injecting the male and female mice with a sub-lethal dose of Lipopolysaccharide weekly for six weeks. The results showed that normal male mice did not show cofilin pathway dysregulation, but a significant dysregulation was observed in CSI advanced-aged mice. In females, cofilin1 dysregulation was observed in healthy and CSI advanced-aged mice, while significant cofilin1 dysregulation was observed in middle-aged mice during CSI. Furthermore, cofilin1 pathway dysregulations correlated with Alzheimer's disease (AD) biomarkers in the brain and saliva, astrocyte activation, synaptic degeneration, neurobehavioral impairments, gut-microbiota abnormalities, and circulatory inflammation. These results provide new insights into cofilin1 sex and age-dependent mechanistic differences that might help identify targets for modulating neuroinflammation and early onset of AD.

2024-12-01·European Journal of Medicinal Chemistry

Design, synthesis and biological evaluation of novel benzimidazole-derived p21-activited kinase 4 (PAK4) inhibitors bearing a 4-(4-methylpiperazin-1-yl)phenyl scaffold as potential antitumor agents

Article

作者: Cai, Zheng-hao ; Hao, Shuang ; Niu, Yi-Fan ; Niu, Yi-fan ; Meng, Fan-Hao ; Wang, Jia-hui ; Yan, Jing-Han ; Meng, Fan-hao ; Li, Feng ; Yan, Jing-han ; Hou, Liang ; Cai, Zheng-Hao ; Wang, Jia-Hui

A series of novel 6-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazole-based p21-activited kinase 4 (PAK4) inhibitors were designed and synthesized based on the structure of lead compound GNE-2861 and that of anticancer inhibitors reported in our previous studies. All target compounds so designed were preliminarily screened in vitro for anti-tumor potency through kinase inhibitory assays and MTT assays, which revealed that most compounds exhibited significant inhibitory effects on PAK4 enzyme as well as prominent antiproliferative activities against four cancer cell models (A549, NCI-H1975, MDA-MB-231 and SK-BR-3) and low damage to healthy cells. In particular, the hit compound 12i was identified as the most effective and rather selective compound both at the enzyme and cellular level. Meanwhile, molecular docking and dynamic studies disclosed that compound 12i could bind to PAK4 stably via multiple interactions applied between the compound and the enzyme. Further mechanism studies indicated that compound 12i could inhibit the proliferation and suppress the migratory potential of MDA-MB-231 cells by inhibiting the phosphorylation of PAK4 and LIMK1, arresting cell cycle in the G0/G1 phase, inducing apoptosis and promoting ROS production. Notably, compound 12i could effectively inhibit triple-negative breast cancer (TNBC) growth with little toxicity in the MDA-MB-231 cell xenograft model. Taken together, in vitro and in vivo results demonstrated that compound 12i possessed high drug potential as an inhibitor of PAK4 to inhibit the growth and metastasis of TNBC.

项与 LIMK1 相关的新闻（医药）

2022-07-25

·生物谷

非编码RNA: 阻断miR-181b和增加Sema3A是房颤治疗干预的潜在策略

心房颤动(房颤)是最常见的持续性心律失常，导致发病率和死亡率的增加。持续性长期房颤以严重的心房肌细胞重构和心房纤维化为特征，无论是抗心律失常药物还是导管消融术都难以达到节律控制的目的。心房颤动(房颤)是最常见的持续性心律失常，导致发病率和死亡率的增加。持续性长期房颤以严重的心房肌细胞重构和心房纤维化为特征，无论是抗心律失常药物还是导管消融术都难以达到节律控制的目的。心房纤维化有助于房颤的维持，是导致房颤难以节律控制的重要因素之一。各种刺激通过增加促纤维化介质的系统或旁分泌表达，如转化生长因子-β，从而引起心房纤维化，包括心力衰竭、糖尿病、剧烈运动和高血压。心房纤维化是心房颤动(AF)的重要因素。经历内皮-间充质转化(EndMT)的心房内膜内皮细胞(AEECs)是否为心房成纤维细胞的来源尚不清楚。图片来源: https://doi.org/10.1172/JCI142548. 近日，来自长庚纪念医院的研究者们在J Clin Invest.杂志上发表了题为“miR-181b targets semaphorin 3A to mediate TGF-β–induced endothelial-mesenchymal transition related to atrial fibrillation”的文章，该研究提供了转化生长因子-β通过miR-181b/Sema3A/LIMK/p-cofilin信号诱导的EndMT与心房纤维化之间的机制联系。阻断miR-181b和增加Sema3A是房颤治疗干预的潜在策略。在本研究中，研究者探索了人的心房、转化生长因子-β处理的人血管内皮细胞、心脏特异的转化生长因子-β转基因小鼠和心力衰竭兔，以确定EndMT在心房纤维化中的潜在机制。利用分离的血管内皮细胞，研究者发现在转化生长因子-β处理的血管内皮细胞中诱导了miR-181b，减少了信号素3A(Sema3A)，增加了EndMT标志物，这些作用可以被miR-181b异构体逆转。在AEECs中，Sema3A被多肽增加或被siRNA减少的实验揭示了Sema3A与Lim-Kins1/p-cofilin(LIMK/p-cofilin)信号之间的机制联系，并提示Sema3A是通过p-cofilin调节肌动蛋白重塑的LIMK上游。给转化生长因子-β转基因小鼠注射miR181bantagomir或重组Sema3A可引起Sema3A增加，EndMT标志物减少，并显著减少心房纤维化和房颤易感性。转化生长因子-β诱导的心内膜下纤维化过程中miR-181b和Sema3A的连接机制示意图图片来源: https://doi.org/10.1172/JCI142548 房颤和各种潜在的全身性疾病促进了心房纤维化，这使得长时间房颤患者很难实现节律控制。房颤时积聚的活化的心房成纤维细胞的来源仍很不清楚。本研究阐明了miR-181b和Sema3A在转化生长因子-β诱导的心内膜下纤维化和心房内膜下纤维化中的作用机制。本研究工作表明，miR-181b antagomir逆转了转化生长因子-β转基因小鼠的心房内膜下纤维化，并降低了房颤的易感性。这项研究确定了一个我们认为是以前未知的途径，即转化生长因子-β/miR-181b/Sema3A/Limk/p-cofilin，并将miR-181b和Sema3A确定为治疗和预防房颤的潜在治疗靶点。（生物谷 Bioon.com）参考文献 Ying-Ju Lai et al. miR-181b targets semaphorin 3A to mediate TGF-β–induced endothelial-mesenchymal transition related to atrial fibrillation. J Clin Invest. 2022 Jul 1;132(13):e142548. doi: 10.1172/JCI142548.