更新于：2024-09-19

LIMK1

更新于：2024-09-19

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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614

项与 LIMK1 相关的文献（医药）

2024-11-01·International Immunopharmacology

NINJ1: A new player in multiple sclerosis pathogenesis and potential therapeutic target

Review

作者: Zhou, Shengjun ; Huang, Yi ; Wei, Liangzhe ; Chen, Siqi ; Zhang, Enhao ; Xu, Yinbin ; Dai, Zifeng

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination. Current treatment options for MS focus on immunosuppression, but their efficacy can be limited. Recent studies suggest a potential role for nerve injury-induced protein 1 (NINJ1) in MS pathogenesis. NINJ1, a protein involved in cell death and inflammation, may contribute to the infiltration and activation of inflammatory cells in the CNS, potentially through enhanced blood-brain barrier crossing; enhancing plasma membrane rupture during cell death, leading to the release of inflammatory mediators and further tissue damage. This review explores the emerging evidence for NINJ1's involvement in MS. It discusses how NINJ1 might mediate the migration of immune cells across the blood-brain barrier, exacerbate neuroinflammation, and participate in plasma membrane rupture-related damage. Finally, the review examines potential therapeutic strategies targeting NINJ1 for improved MS management. Abbreviations: MS, Multiple sclerosis; CNS, Central nervous system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma membrane rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated molecular patterns; PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis factor; APCs, Antigen-presenting cells; ECs, Endothelial cells; TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear cells; FACS, Fluorescence-activated cell sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T cell receptor; ROS, Reactive oxygen species; AP-1, Activator protein-1; ANG1, Angiopoietin 1; BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related protein 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase 1; PAK1, p21-activated kinases 1; Rac1, Ras-related C3 botulinum toxin substrate 1; β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor domain-containing adapter protein; TLR4, Toll-like receptor 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF receptor associated factor 6; TAB2/3, TAK1 binding protein 2/3; TAK1, transforming growth factor-β-activated kinase 1; JNK, c-Jun N-terminal kinase; ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa-B; AP-1, activator protein-1; ASC, Apoptosis-associated Speck-like protein containing a CARD; NEK7, NIMA-related kinase 7; NLRP3, Pyrin domain-containing 3; CREB, cAMP response element-binding protein.

2024-10-01·Pharmacological Research

LIM kinase 2 activates cardiac fibroblasts and exacerbates postinfarction left ventricular remodeling via crosstalk between the canonical and non-canonical Wnt pathways

Article

作者: Liu, Yihai ; Sun, Xuan ; Wang, Lian ; Xu, Biao ; Huang, Rong ; Gong, Chenyi ; Chang, Lei ; Wang, Lintao ; Wu, Shaojun

Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of β-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-β treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-β-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.

2024-07-23·Journal of Virology

RABV induces biphasic actin cytoskeletal rearrangement through Rac1 activity modulation

Article

作者: Xu, Jing ; Guo, Xin ; Zhang, Maolin ; Guan, Zhenhong ; Wang, Hualei ; Guo, Yidi ; Duan, Ming ; Zhao, Mingxin ; Liu, Xiaomin

ABSTRACTRabies virus (RABV) is highly lethal and triggers severe neurological symptoms. The neuropathogenic mechanism remains poorly understood. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a Rho-GTPase that is involved in actin remodeling and has been reported to be closely associated with neuronal dysfunction. In this study, by means of a combination of pharmacological inhibitors, small interfering RNA, and specific dominant-negatives, we characterize the crucial roles of dynamic actin and the regulatory function of Rac1 in RABV infection, dominantly in the viral entry phase. The data show that the RABV phosphoprotein interacts with Rac1. RABV phosphoprotein suppress Rac1 activity and impedes downstream Pak1-Limk1-Cofilin1 signaling, leading to the disruption of F-actin-based structure formation. In early viral infection, the EGFR-Rac1-signaling pathway undergoes a biphasic change, which is first upregulated and subsequently downregulated, corresponding to the RABV entry-induced remodeling pattern of F-actin. Taken together, our findings demonstrate for the first time the role played by the Rac1 signaling pathway in RABV infection and may provide a clue for an explanation for the etiology of rabies neurological pathogenesis.IMPORTANCEThough neuronal dysfunction is predominant in fatal rabies, the detailed mechanism by which rabies virus (RABV) infection causes neurological symptoms remains in question. The actin cytoskeleton is involved in numerous viruses infection and plays a crucial role in maintaining neurological function. The cytoskeletal disruption is closely associated with abnormal nervous symptoms and induces neurogenic diseases. In this study, we show that RABV infection led to the rearrangement of the cytoskeleton as well as the biphasic kinetics of the Rac1 signal transduction. These results help elucidate the mechanism that causes the aberrant neuronal processes by RABV infection and may shed light on therapeutic development aimed at ameliorating neurological disorders.

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.libproxy1.nus.edu.sg/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.libproxy1.nus.edu.sg/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.