更新于：2024-11-01

MAP3K20

更新于：2024-11-01

基本信息

别名

HCCS-4、Human cervical cancer suppressor gene 4 protein、Leucine zipper- and sterile alpha motif-containing kinase

+ [13]

简介

Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:32610081, PubMed:32289254, PubMed:35857590, PubMed:26999302). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32610081, PubMed:32289254, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622). Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32610081, PubMed:32289254, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32610081, PubMed:32289254). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32610081, PubMed:32289254). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425). Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32610081, PubMed:32289254, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).

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100 项与 MAP3K20 相关的临床结果

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100 项与 MAP3K20 相关的转化医学

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0 项与 MAP3K20 相关的专利（医药）

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191

项与 MAP3K20 相关的文献（医药）

2024-07-01·Cell

The ribotoxic stress response drives UV-mediated cell death

Article

作者: Yaron-Barir, Tomer M ; Johnson, Jared L ; Huntsman, Emily M ; Li, Jeffrey J ; Sinha, Niladri K ; Green, Rachel ; Yeow, Zhong Y ; Regot, Sergi ; Ordureau, Alban ; McKenney, Connor ; Nam, Ki Hong ; Cantley, Lewis C

While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.

2024-05-01·Life Science Alliance

Interrogating endothelial barrier regulation by temporally resolved kinase network generation

Article

作者: Vijayan, Kamalakannan ; Smith, Joseph D ; Dankwa, Selasi ; Kaushansky, Alexis ; Wei, Ling

Kinases are key players in endothelial barrier regulation, yet their temporal function and regulatory phosphosignaling networks are incompletely understood. We developed a novel methodology, Temporally REsolved KInase Network Generation (TREKING), which combines a 28-kinase inhibitor screen with machine learning and network reconstruction to build time-resolved, functional phosphosignaling networks. We demonstrated the utility of TREKING for identifying pathways mediating barrier integrity after activation by thrombin with or without TNF preconditioning in brain endothelial cells. TREKING predicted over 100 kinases involved in barrier regulation and discerned complex condition-specific pathways. For instance, the MAPK-activated protein kinase 2 (MAPKAPK2/MK2) had early barrier-weakening activity in both inflammatory conditions but late barrier-strengthening activity exclusively with thrombin alone. Using temporal Western blotting, we confirmed that MAPKAPK2/MK2 was differentially phosphorylated under the two inflammatory conditions. We further showed with lentivirus-mediated knockdown of MAPK14/p38α and drug targeting the MAPK14/p38α-MAPKAPK2/MK2 complex that a MAP3K20/ZAK-MAPK14/p38α axis controlled the late activation of MAPKAPK2/MK2 in the thrombin-alone condition. Beyond the MAPKAPK2/MK2 switch, TREKING predicts extensive interconnected networks that control endothelial barrier dynamics.

2024-05-01·eneuro

Functional Recovery Associated with Dendrite Regeneration in PVD Neuron ofCaenorhabditis elegans

Article

作者: Pande, Devashish ; Ghosh-Roy, Anindya ; Brar, Harjot Kaur ; Singh, Pallavi ; Dey, Swagata

PVD neuron ofCaenorhabditis elegansis a highly polarized cell with well-defined axonal, and dendritic compartments. PVD neuron operates in multiple sensory modalities including the control of both nociceptive touch sensation and body posture. Although both the axon and dendrites of this neuron show a regeneration response following laser-assisted injury, it is rather unclear how the behavior associated with this neuron is affected by the loss of these structures. It is also unclear whether neurite regrowth would lead to functional restoration in these neurons. Upon axotomy, using a femtosecond laser, we saw that harsh touch response was specifically affected leaving the body posture unperturbed. Subsequently, recovery in the touch response is highly correlated to the axon regrowth, which was dependent on DLK-1/MLK-1 MAP Kinase. Dendrotomy of both major and minor primary dendrites affected the wavelength and amplitude of sinusoidal movement without any apparent effect on harsh touch response. We further correlated the recovery in posture behavior to the type of dendrite regeneration events. We found that dendrite regeneration through the fusion and reconnection between the proximal and distal branches of the injured dendrite corresponded to improved recovery in posture. Our data revealed that the axons and dendrites of PVD neurons regulate the nociception and proprioception in worms, respectively. It also revealed that dendrite and axon regeneration lead to the restoration of these differential sensory modalities.

项与 MAP3K20 相关的新闻（医药）

2024-07-17

·生物探索

Cell | 核糖毒性应激反应驱动紫外线介导的细胞程序性死亡

引言紫外线（UV）辐射会诱导DNA损伤并激活DNA损伤反应（DDR）途径，从而阻滞细胞周期为DNA修复留出时间，当DNA损伤严重到难以修复时就会激活细胞凋亡【1-3】。UV辐射诱导DNA损伤的研究早已被人们熟知，但是关于UV也可以诱导RNA损伤的产生却较少被提及。有研究发现，UV可以通过光化学反应生成嘧啶二聚体和其他光产物，这些产物可以诱导转录组范围内的RNA损伤，同时UV损伤还会导致翻译缺陷，核糖体会停滞在富含嘧啶的受损密码子上，引起核糖体碰撞，从而激活核糖毒性应激反应（ribotoxic stress response, RSR）【4-5】。RSR将会激活下游的ZAK和GCN2激酶，ZAK激酶激活MAPK途径介导细胞周期停滞和细胞凋亡，GCN2激酶的激活导致eIF2α磷酸化和通过整合应激反应（ISR）介导的蛋白合成抑制【6-10】。虽然已经发现UV诱导的RNA损伤可以通过核糖体碰撞激活RSR和ISR通路，但是这些研究未能解决一个关键问题：细胞如何整合这些反应来决定细胞的命运。 7月11日，来自美国约翰霍普金斯大学医学院的Rachel Green课题组在Cell上发表了研究论文The ribotoxic stress response drives UV-mediated cell death。在本研究中，作者通过全面的分析揭示了UV照射后细胞内发生的各种核酸损伤应激反应作用，发现RSR在UV依赖的程序性细胞死亡中比DDR起到更为关键的作用。这一发现突破了传统的认知，为理解细胞如何应对UV损伤提供了新的见解。为了阐明这个问题，作者首先研究了细胞对UV强度做出的分级反应，在较低强度UV辐射时细胞主要停滞在G2期，死亡细胞极少；而较高UV强度则导致凋亡细胞比例显著增加。在低剂量UV照射后数分钟内可以观察到核糖体碰撞的积累，并在几个小时内被清除。对低剂量UV照射后RSR、ISR和DDR三种信号通路的激活动力学进行分析发现：（1）代表RSR途径的ZAK激酶几分钟内就被磷酸化并在15分钟时达到峰值，与此同时ZAK下游的p38和JNK快速被激活，表明RSR途径在早期响应中高度协同；（2）ISR途径中的eIF2α在UV照射后早期被磷酸化并不断增加，说明ISR信号通路在应对UV照射后逐渐增强；（3）DDR的效应分子磷酸化速度较慢，显示出与RSR和ISR不同的激活模式。作者还通过磷酸化和蛋白质组学分析也进一步证实了这一发现，即UV照射不同应激反应的顺序激活模式，并强调了核糖体介导的信号转导在最早期的主导地位。接下来，作者分别详细的研究了ZAK和GCN2在UV处理后对磷酸化蛋白质组变化的作用。通过敲除ZAK或GCN2，以及使用两种激酶的特异性抑制剂处理，作者研究发现ZAK在早期响应中起着关键作用，而GCN2在p38效应激酶的调控中发挥重要作用。此外，RSR和DDR信号通路在UV响应过程中是独立运行的，因为使用DDR效应激酶ATR的抑制剂处理可以发现DDR特异性磷酸化位点与ZAK激酶依赖的磷酸化位点没有相关性。对ZAK和ATR在决定细胞命运中的作用进行分析后，作者发现ZAK主要驱动UV响应的早期凋亡和G2/M检测点激活，而ATR在细胞增殖和DNA修复中起到了关键作用。相对应的是，GCN2通过磷酸化eIF2α和抑制mTOR活性来阻止翻译起始，从而限制受损mRNA上核糖体碰撞的积累；缺乏GCN2的细胞表现出更高的核糖体碰撞和RSR（ZAK）的过度激活，导致JNK信号通路的持续高活性和更高的细胞凋亡率；并且ZAK和GCN2在调控细胞应对UV损伤中的作用独立且互不影响。在确定核糖体碰撞是如何激活RSR之后，作者将目光聚焦到RSR信号转导的衰减上。对此，作者分析了ZAK在响应RSR时的激活和降解机制。研究发现，ZAK的激活涉及多种磷酸化位点的动态变化，而降解主要通过CRL1 E3泛素连接酶复合物介导，ZAK的自磷酸化位点在降解时发挥了重要作用。并且ZAK的多结构域使其能够在响应核糖体碰撞时发挥复杂的调控功能。最后，作者探究了RSR信号转导的衰减是如何影响细胞命运的决定。通过一些列实验和分析，作者发现ZAK降解通过负反馈调控JNK信号，减少细胞凋亡，并使细胞对持续的核糖毒性应激产生耐受性。模式图（Credit: Cell）总的来说，这篇文章系统的研究了UV辐射诱导核酸损伤后的多种应激反应激活模式，揭示了各个途径在细胞命运决定的重要作用，特别是在细胞经历核糖体碰撞和核糖毒性应激时的细胞命运是如何被驱动的。深入研究了ZAK的激活和降解机制，有助于以此为靶标开发新药物来调节细胞应激反应，这对于治疗与应激响应失调相关的疾病具有重要潜力。参考文献 1. Mare ́ chal, A., and Zou, L. (2013). DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 5, a012716. 2. Zhou, B.B., and Elledge, S.J. (2000). The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439. 3. Saldivar, J.C., Cortez, D., and Cimprich, K.A. (2017). The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat. Rev. Mol. Cell Biol. 18, 622–636. 4. Wurtmann, E.J., and Wolin, S.L. (2009). RNA under attack: Cellular handling of RNA damage. Crit. Rev. Biochem. Mol. Biol. 44, 34–49. 5. Wu, C.C.-C., Peterson, A., Zinshteyn, B., Regot, S., and Green, R. (2020). Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell 182, 404–416.e14. 6. Jandhyala, D.M., Ahluwalia, A., Obrig, T., and Thorpe, C.M. (2008). ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced proinflammatory cytokine expression. Cell Microbiol. 10, 1468–1477. 7. Sauter, K.A.D., Magun, E.A., Iordanov, M.S., and Magun, B.E. (2010). ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells. Cancer Biol. Ther. 10, 258–266. 8. Wang, X., Mader, M.M., Toth, J.E., Yu, X., Jin, N., Campbell, R.M., Smallwood, J.K., Christe, M.E., Chatterjee, A., Goodson, T., et al. (2005). Complete Inhibition of Anisomycin and UV Radiation but Not Cytokine Induced JNK and p38 Activation by an Aryl-substituted Dihydropyrrolopyrazole Quinoline and Mixed Lineage Kinase 7 Small Interfering RNA. J. Biol. Chem. 280, 19298–19305. 9. Stoneley, M., Harvey, R.F., Mulroney, T.E., Mordue, R., Jukes-Jones, R., Cain, K., Lilley, K.S., Sawarkar, R., and Willis, A.E. (2022). Unresolved stalled ribosome complexes restrict cell-cycle progression after genotoxic stress. Mol. Cell 82, 1557–1572.e7. 10. Vind, A.C., Snieckute, G., Blasius, M., Tiedje, C., Krogh, N., Bekker-Jensen, D.B., Andersen, K.L., Nordgaard, C., Tollenaere, M.A.X., Lund, A.H., et al. (2020). ZAKa Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. Mol. Cell 78, 700–713.e7. https://doi.org/10.1016/j.cell.2024.05.018 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-07-02

·Science Daily

UV radiation damage leads to ribosome roadblocks, causing early skin cell death

In a recent study, researchers suggest the cell's messenger RNA (mRNA) -- the major translator and regulator of genetic material -- along with a critical protein called ZAK, spur the cell's initial response to UV radiation damage and play a critical role in whether the cell lives or dies. In a recent study, researchers at Johns Hopkins Medicine suggest the cell's messenger RNA (mRNA) -- the major translator and regulator of genetic material -- along with a critical protein called ZAK, spur the cell's initial response to UV radiation damage and play a critical role in whether the cell lives or dies. While UV radiation has long been known to damage DNA, it also damages mRNA, and the latest findings, published June 5 in Cell, indicate that mRNAs act as first responders in telling the cells how to manage the stress. "RNA is a canary in the coal mine. It's telling the cell, 'We've got major damage here and we need to do something,'" says Rachel Green, Ph.D., a Bloomberg Distinguished Professor of Molecular Biology and Genetics and Daniel Nathans Director of the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. Green, also an investigator at Howard Hughes Medical Institute, is the corresponding author of the new study. ZAK is a key player in a process that identifies cellular damage by sensing the collisions of ribosomes, tiny macromolecular machines that help RNA translate the language of genes into the language of proteins. Collisions occur when ribosomes move along UV-damaged mRNAs and, unable to decode the damaged message, cause stalled ribosomes to get "rear-ended" by upstream ribosomes. Ribosome collisions activate ZAK, which triggers a cellular signaling program known as the ribotoxic stress response. ZAK then instigates a cascade of downstream events that decide the cell's fate. A more comprehensive understanding of how cellular life-and-death decisions are made upon encountering UV radiation could help investigators understand underlying causes of skin and other cancers, says Niladri Sinha, Ph.D., Jane Coffin Childs Memorial Fund Postdoctoral Fellow at Johns Hopkins School of Medicine. Companies developing drugs that target ribosomes may also find that ZAK could be a driver of cell death across cancer types, he says. The findings indicate that ZAK senses the extent of cellular damage and responds depending on how much UV radiation the cell receives, offering a more nuanced understanding of UV-caused cell death and identifying new ways to keep ZAK's activity under control, Green says. "There are graded ways that ZAK responds, it's not all or nothing," she says. The research also "very clearly shows" that, for example, a skin cell's fate in the immediate aftermath of UV radiation is "driven primarily by the extent of colliding ribosomes and ZAK signaling," Green says. "In this regime, DNA damage and the well-characterized DNA damage response pathway, including the key protein p53, do not significantly determine cell fate decisions," she says. DNA damage repair is critical and occurs in a subset of cells that are copying their genetic material, but these pathways are not the major "deciders" of cell fate, she says. Green co-led the research with Sergi Regot, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, and Alban Ordureau, Ph.D., assistant member of the Cell Biology Program at Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute and an assistant professor at Weill Cornell. To conduct their research, the scientists exposed human cellular models to a UV lamp mimicking the sun's radiation. Using proteomics to understand cell signaling in an approach led by Ordureau, they evaluated ZAK's role and made predictions about how cells would respond to different levels of stress. From there, live cell imaging experiments led by Regot, in addition to in-house ribosome biochemistry -- the workhorse of Green's laboratory -- helped characterize how cellular death is regulated as a consequence of ZAK-mediated UV radiation. In the future, the researchers plan to investigate cell types with different protein synthesis regimes, including those in melanoma and other cancers. The researchers suspect that fast-growing cells will rely on ZAK-mediated regulation more than others, Green says. Funding for this research was provided by the Howard Hughes Medical Institute, the National Institutes of Health (NIH 1R35GM133499), a National Science Foundation Career grant, the Jane Coffin Childs Memorial Fund for Medical Research Fellowship, and the National Institute of General Medical Sciences, Sloan Kettering Institute startup funds, Pew Charitable Trusts, a Memorial Sloan Kettering Cancer Center support grant, and the Basic Science Research Program from the National Research Foundation of Korea; Ministry of Education. Other scientists who contributed to this study are Connor McKenney, Zhong Y. Yeow, and Jeffrey J. Li of Johns Hopkins; Ki Hong Nam of Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute; and Tomer M. Yaron-Barir, Jared L. Johnson, Emily M. Huntsman and Lewis C. Cantley of Weill Cornell Medicine. Green is a member of the scientific advisory board of Alltrna, Initial Therapeutics and Arrakis Pharmaceuticals, consults for Vertex Pharmaceuticals, Bristol-Myers Squibb (Celgene), Monta Rosa Therapeutics and Flagship Pioneering, and served on the scientific advisory board at Moderna.

放射疗法

2024-05-30

·精准药物

药物筛选中心（暨南大学）对外提供新药筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、COX、GPCR、报告基因、病毒、细菌等筛选模型，能够开展肿瘤、神经系统疾病、心脑血管病、糖尿病、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）蛋白水平：激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK。蛋白酶：MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MMP-14, ADAM5, ADAM10, ADAMTS13, TACE/ADAM17, Furin, Cathepsin E, Cathepsin D, BACE-1, DDP4, DDP8, DDP9, HIV protease-1, PMVII，PMVIV。HDACs：HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6。2）肿瘤细胞活性：近500种肿瘤细胞系；基于Ba/F3的耐药模型3）抗病毒/菌药物筛选：EV71和HSV病毒活性筛选模型；金黄色葡萄球菌、大肠杆菌和沙门氏杆菌等4）体内药效：移植瘤模型对外服务1）体外活性筛选（单剂量抑制率；多剂量IC50）；2）体内药效；3）机制研究；4）药代动力学研究；5）化合物工艺优化、大量订制。咨询合作

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