关键词： autoimmunity   CD4(+) T cells   cosignaling   T-cell inflammation   TNFRSF  

摘要： A costimulatory signal from the tumor necrosis factor receptor (TNFR) family molecule OX40 (CD134), which is induced on activated T cells, is important for T-cell immunity. Aberrant OX40 cosignaling has been implicated in autoimmune and inflammatory disorders. However, the molecular mechanism by which the OX40 cosignaling regulates the T-cell response remains obscure. We found that OX40 associated with a scaffold protein, IQ motif-containing GTPase-activating protein 1 (IQGAP1) after ligation by its ligand OX40L. Naive CD4(+) T cells from Iqgap1(-/-) mice displayed enhanced proliferation and cytokine secretion upon receiving OX40 cosignaling. A C-terminal IQGAP1 region was responsible for its association with OX40, and TNFR-associated factor 2 (TRAF2) bridged these two proteins. The enhanced cytokine response in Iqgap1(-/-) T cells was restored by the expression of the C-terminal IQGAP1. Thus, the IQGAP1 binding limits the OX40 cosignaling. Disease severity of experimental autoimmune encephalomyelitis (EAE) was significantly exacerbated in Iqgap1(-/-) mice as compared to wild-type mice. Additionally, recipient mice with Iqgap1(-/-) donor CD4(+) T cells exhibited significantly higher EAE scores than those with their wild-type counterparts, and OX40 blockade led to a significant reduction in the EAE severity. Thus, our study defines an important component of the OX40 cosignaling that restricts inflammation driven by antigen-activated T cells.

关键词： 肺微血管内皮细胞   IQGAP1   埃兹蛋白   通透性   RNA干扰  

摘要： 研究背景及目的急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)由多种传染性和无菌性病因,例如肺炎,胃内容物吸入,败血症,急性肝衰竭和急性胰腺炎等直接或间接引起肺损伤的致命疾病,发生和发展过程复杂,发病机理尚未完全阐明。潜在的发病机制可能归因于中性粒细胞积聚和促炎性细胞因子作用于肺微血管内皮细胞(PMVECs),导致细胞间连接的破坏(例如粘附连接),微管激活和肌动蛋白细胞骨架重塑,细胞收缩并形成间隙,炎症破坏肺微血管屏障,大量蛋白质和液体进入肺间质和肺泡腔,发生临床上严重的低氧血症性呼吸衰竭。研究表明,单一的阻断炎症介质并未取得理想效果,探究ARDS过程中相关的信号通路,阻断炎症风暴发生,是目前关注的新热点。Rac1作为小G蛋白家族一员,在稳定肌动蛋白的细胞骨架和维持微血管屏障功能方面发挥重要作用。Rac1通过促进皮质区肌动蛋白纤维束的形成来调节细胞骨架,通过连接复合物的重塑来维持细胞间连接。有证据表明,抑制Rac1可显著增加静脉微血管通透性。膜-F-肌动蛋白连接蛋白Ezrin与支架蛋白IQGAP1共定位于膜下细胞骨架,是聚集不同信号复合物的枢纽。近几年人们也开始研究它们在内皮通透性方面作用,但炎症条件下,它们究竟对细胞屏障有何影响,尚未见报道。F-肌动蛋白介导的粘附连接,是维持内皮屏障的关键因素,皮质肌动蛋白结合蛋白(cortactin)通过增加自身其在细胞皮质中的分布,促进其与皮质肌动蛋白细胞骨架的结合,从而增强粘附和紧密连接,调节细胞骨架的动力学,参与内皮屏障功能的调节。TNF-α是ARDS在疾病早期阶段分泌的主要促炎细胞因子。它通过改变内皮细胞紧密连接的结构和F-肌动蛋白的分布来破坏内皮细胞屏障的功能完整性。*本实验系国家自然科学基金资助项目(No.81770081)本研究拟通过TNF-α刺激PMVEC,破坏细胞屏障,并分别抑制Rac1、IQGAP1、Ezrin表达,观察它们在TNF-α致伤大鼠PMVEC中的作用。方法1.体外分离、培养、鉴定、传代RPMVECs。2.取已提前铺好胶的transwell小室若干,按制定的实验方案,构建相应的体外RPMVECs单层细胞模型。按照制定的实验分组给予细胞不同的刺激,检测跨内皮细胞电阻(transendothelial electrical resistance,TEER)变化和异硫氰酸荧光素标记的白蛋白(FITC-BSA)的通透性变化。3.给予不同浓度或品种试剂刺激RPMVECs,倒置荧光显微镜观察细胞骨架蛋白F-actin和cortactin的变化。4.通过western blot检测不同实验分组中Rac1、IQGAP1、Ezrin、cortactin水平改变。5.分别构建靶向Rac1、IQGAP1、Ezrin的载体质粒,并包装相应慢病毒感染RPMVECs,分别下调这三者的表达。6.分别检测下调Rac1、IQGAP1、Ezrin表达后,TEER、FITC-BSA及细胞骨架的变化。结果1.体外成功分离、培养RPMVECs(约10-14天),经显微镜下细胞形态学、FITC-植物血凝素结合试验鉴定证实。2.通过CCK8实验发现,当TNF-α浓度为0、1、10和100 ng/m L时对PMVECs细胞活性无显著影响。测细胞通透性发现,TEER呈剂量依赖性(1-100 ng/m L)和时间依赖性(0-6 h)下降。TNF-α刺激2 h后的FITC-BSA通透率也随着TNF-α浓度升高而升高。3.原代RPMVECs感染慢病毒后,倒置荧光显微镜下48 h即可见绿色荧光蛋白(GFP)表达,72 h后GFP表达强度进一步增强。感染效率,即72 h末占初始值比例:Rac1-sh RNA 15±7%,IQGAP1-sh RNA 10±1.1%,Ezrin-sh RNA 35±3.16%,阴性对照组三种蛋白表达无显著变化。***-α(100 ng/m L)刺激PMVECs后,Rac1的活性(Rac1-GTP)以时间依赖性(0-2 h)方式显著降低,而Rac1总的表达水平却保持不变。Rac1下调,细胞的TEER降低至对照组的约57%,用TNF-α刺激2 h后,sh Rac1组细胞的TEER降至36%,而control-sh RNA组的TEER降至61%。相反,若给予8-O-Me-c AMP(200 mmo L/L)预孵育,TNF-α组的TEER增加至130%,在3 h末仍稍高于对照组。FITC-BSA渗透率也显示出相似的通透性变化。***-α作用于细胞,可见F-actin聚集,细胞外周cortactin的分布减少。无论是否暴露于TNF-α,Rac1表达受到抑制后,PMVEC细胞内均会出现高应力纤维、细胞表面的cortactin水平显著下降。经

摘要： The dissertation is composed of two sections. The first section is composed of chapters one, two, and three and describes the study of macrocyclic β-hairpin peptides derived from β-sheet peptides. The second section is composed of chapters four and five and discusses the curricular innovations made to support the remote instruction of an organic chemistry lecture course, a general chemistry laboratory course, and an organic chemistry laboratory course at the onset of the COVID-19 pandemic. Chapter 1 describes the use of acetylation as a means to modulate and study the effect of charge on the oligomeric assembly and toxicity of familial Alzheimer’s disease (FAD) mutants of Aβ. FAD is an inherited form of Alzheimer’s disease that has an earlier onset due to point mutations within the sequence of Aβ that alter the rate of aggregation and toxicity of the peptide. The most common site of these mutations is position 22 in which the native glutamic acid may be replaced with a glycine (E22G), glutamine (E22Q), or lysine (E22K). Previous work in our lab using a macrocyclic chemical model system of the Aβ peptide that incorporates residues 16-22 and 30-36 established that there was a correlation between the net charges of these mutant peptides and their oligomeric assemblies and toxicities as measured by SDS-PAGE, LDH-release assays, and dye leakage assays. In this chapter I further probe the effect of charge on the oligomeric assembly and toxicity of the FAD mutant peptides using our lab’s chemical model system of Aβ. To control for the hydrophobicity and size of the residues that vary between the mutants, I used acetylation as a tool to manipulate the net charge of the peptides. This work demonstrates that the toxicities of the peptides strongly correlate with their net charges based on LDH-release assays and dye leakage assays. The oligomeric assemblies of the peptides assessed by SDS-PAGE suggest that charge is a factor that impacts their assembly, but that the position o

关键词： circFBXW4   缺血性脑卒中   星形胶质细胞   HECTD1   IQGAP1   自噬  

摘要： 目的:缺血性脑卒是导致死亡和残疾的主要原因。虽然过去几十年中开发了多种新的实验性神经保护策略,但在临床转化上仍面临着很大的困难。因此,寻找新的治疗靶点以作为脑卒中溶栓治疗的辅助疗法仍是临床所需要的。环状RNA(circRNA)在中枢神经系统中高度表达,其功能失调涉及多种神经系统疾病。本课题组的前期研究表明,抑制circTLK1的表达可以减轻缺血性脑卒中后神经元损伤,促进神经功能恢复,而过表达circDLGAP4则可以保护卒中后血脑屏障的完整性。然而,circRNA在缺血性脑卒中病理进展中的潜在作用仍未阐明。本研究发现在急性缺血性脑卒中(acute ischemic stroke,AIS)患者血浆中circRNA FBXW4(circFBXW4)表达显著下调,因此本研究以circFBXW4为切入点,旨在探究circFBXW4在缺血性脑卒中的作用及机制,揭示了circRNA作为脑卒中生物标志物的潜力,并为脑卒中治疗靶点的开发提供理论依据。方法:(1)应用circRNA微阵列技术筛选AIS患者血浆中差异表达的circRNA。(2)应用Real-time PCR方法在AIS患者血浆以及短暂性大脑中动脉闭塞模型(transient middle cerebral artery occlusion,tMCAO)小鼠血浆和脑组织中验证大数据结果。(3)小鼠脑微注射circFBXW4过表达慢病毒后进行tMCAO造模,应用2,3,5—氯化三苯基四氮唑(2,3,5-triphenyltetrazolium chloride,TTC)染色检测tMCAO小鼠脑梗死体积;在复灌后3,7,14,21,28天检测小鼠行为学和神经功能学评分。(4)荧光原位杂交技术检测circFBXW4在小鼠脑内细胞的分布。(5)应用超高速离心分离肉瘤融合/脂肪肉瘤转运蛋白(fused in sarcoma/translocated in liposarcoma,FUS/TLS)聚集体并用western blot检测。(6)免疫荧光染色、western blot检测缺血脑组织胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)的表达。(7)在离体细胞水平,利用原代培养的星形胶质细胞制备氧糖剥夺/再灌注(oxygen-glucose deprivation/reperfusion,OGD/R)模型,转染circFBXW4过表达慢病毒后western blot检测HECTD1,LC3B-Ⅱ,IQGAP1等蛋白的表达。结果:(1)circFBXW4在AIS患者血浆和tMCAO小鼠血浆及脑组织中表达降低。(2)过表达circFBXW4显著改善tMCAO小鼠神经功能损伤程度、减小脑梗死体积,促进神经功能恢复。(3)circFBXW4在小鼠脑内主要分布于星形胶质细胞中,过表达circFBXW4抑制tMCAO小鼠脑中GFAP表达增加,抑制星形胶质细胞活化。(4)通过生物信息学分析发现circFBXW4与FUS相互结合,而FUS在缺血性脑卒中后形成聚集体,过表达circFBXW4可抑制缺血损伤导致的FUS聚集。(5)敲低FUS抑制HECTD1的表达,过表达circFBXW4通过FUS/HECTD1轴抑制星形胶质细胞活化。(6)HECTD1泛素化底物IQGAP1在缺血再灌后表达降低,过表达IQGAP1可抑制星形胶质细胞活化,IQGAP1参与circFBXW4介导的星形胶质细胞活化。结论:本论文研究表明,circFBXW4通过结合并吸附FUS,抑制缺血性脑卒中后FUS聚集,增加FUS的游离形式,从而上调下游靶蛋白HECTD1及其泛素化底物IQGAP1的表达,并随后抑制星形胶质细胞活化。本研究结果为circFBXW4在脑缺血中的潜在作用机理提供了新的证据。

关键词： 肺微血管内皮细胞   IQGAP1   脂多糖   RNA-Sequencing   NF-κB  

摘要： 研究背景衬覆于血管内膜表面的肺微血管内皮细胞(pulmonary microvascular endothelial cells,PMVECs)是血液运输屏障的重要组成部分,具有物质交换炎性介质等选择性调节功能;PMVECs在维持内环境动态平衡中也发挥着关键性作用;此外,细胞内、外的信号刺激引起PMVECs功能的变化是影响微血管通透性改变的关键因素。由于微血管内皮细胞结构破坏,通透性增加引起的血管渗漏仍然是导致许多炎症性疾病发病的主要机制之一。急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)的重症患者死亡率接近45%,炎症的过度激活所致PMVECs通透性增加是其主要的病理特征。粘附连接是血管内皮连接的主要方式,可直接调节细胞骨架,与血管内皮通透性密切相关;粘附连接也参与建立和维持细胞间粘附、骨架重塑、信号传导及转录后调控等多种细胞功能。IQGAPs(IQ-domain GTPase-activating proteins,IQGAPs)是一类含有多域结构的真核细胞蛋白家族。作为细胞骨架结合蛋白的IQGAPs在调控胞质分裂、细胞迁移、组织重塑、细胞黏附和细胞信号转导等生物学进程中占有重要地位。IQGAPs蛋白家族包括IQGAP1,IQGAP2和IQGAP3三个成员。IQGAP1分布广泛,除了脑组织外,各组织和器官均有分布,在肺脏表达水平较高。IQGAP1是由1657个氨基酸组成的肌动蛋白调节蛋白,在维持细胞骨架正常粘附功能和细胞间连接中发挥着主要的作用。因此IQGAP1被认为是维护微血管内皮细胞单层通透性和完整性的关键因素之一。近年来,已有研究证实IQGAP1的缺失会影响血管内皮细胞的通透并导致血管渗漏,但是其具体机制以及是否也存在于炎症诱导下肺微血管内皮细胞单层通透性的改变,尚不明确。核因子-κB(nuclear factor kappa B,NF-κB)是Rel/NF-κB家族多肽成员组成的一组诱导型转录因子。在微生物感染、应激、创伤等外界物质刺激下,其活性可以异常升高,导致大量促炎因子的过度释放。目前已有文献报道,在ARDS中NF-κB信号传导通路被激活,参与多种炎症因子的表达,调控ARDS的发生、发展并影响其预后。作为革兰阴性菌细胞壁主要成分的脂多糖(lipopolysaccharide,LPS)不仅可以诱导血管内皮细胞通透性的增加;而且,从目前已知的机制中可以证实,LPS存在激活部分细胞内信号转导通路,损伤内皮细胞间连接,破坏细胞骨架,导致细胞通透性增高。大量临床资料也证实LPS参与ARDS的发生发展,然而NF-κB作为炎症反应基因大量表达的控制点,在LPS诱导PMVECs通透性的改变中被激活,是否能影响IQGAP1的表达变化及其作用机制,目前尚未见相关报道。研究目的本研究以大鼠PMVECs(rat pulmonary microvascular endothelial cells,RPMVECs)表达的IQGAP1为研究对象,在不同干扰因素的影响下,分析IQGAP1的表达以及对PMVECs通透性调控的信号途径和分子机制的影响。在LPS诱导PMVECs单层通透性增加的过程中,初步探讨NF-κB信号通路参与LPS对IQGAP1的调控及机制研究。旨在为诸如ARDS等PMVECs单层通透性改变疾病的机制研究,提供分子生物学实验证据。研究方法1、原代RPMVECs体外分离、培养和鉴定;2、鉴定RPMVECs上IQGAPs的存在及亚型的表达。3、检测LPS诱导RPMVECs中IQGAP1的表达变化。4、体外构建慢病毒感染IQGAP1低表达和过表达的RPMVECs稳定感染细胞并鉴定。5、利用transwell chamber,在体外构建RPMVECs单层细胞模型。用不同浓度和时间的LPS诱导干预RPMVECs单层融合细胞,监测跨内皮细胞电阻(TER)的变化,分析LPS对RPMVECs单层通透性的作用。6、在LPS干预条件下,观察并分析IQGAP1正常表达、低表达和过表达的RPMVECs上骨架蛋白F-actin的变化。7、利用RNA-Sequencing,分析IQGAP1的低表达对RPMVECs中mRNA表达变化的影响,并筛选出有意义的DEGs;通过GO、KEGG等mRNA功能富集分析,探讨与IQGAP1表达相关的关键基因和参与RPMVECs生物学过程的信号通路。8、通过Western blot观察:经si RNA介导NF-κB干扰抑制后,IQGAP1和NF-κB P65的表达情况;经LPS和NF-κB抑制剂CAPE诱导作用下,在IQGAP1低表达、正常表达和过表达情况下,NF-κB P65的表达变化及二者是否具有相关性。9、利用transwell chamber,在体外分别构建

关键词： Peptides and proteins   Genetics   Monomers   Hydrophobicity   Mathematical methods  

摘要： IQ domain GTPase-activating scaffolding protein 1 (IQGAP1) mediates cytoskeleton, cell migration, proliferation, and apoptosis events. Calmodulin (CaM) modulates IQGAP1 functions by binding to its four tandem IQ motifs. Exactly how CaM binds the IQ motifs and which functions of IQGAP1 CaM regulates and how are fundamental mechanistic questions. We combine experimental pull-down assays, mutational data, and molecular dynamics simulations to understand the IQ-CaM complexes with and without Ca2+ at the atomic level. Apo-CaM favors the IQ3 and IQ4 motifs but not the IQ1 and IQ2 motifs that lack two hydrophobic residues for interactions with apo-CaM's hydrophobic pocket. Ca2+-CaM binds all four IQ motifs, with both N- and C-lobes tightly wrapped around each motif. Ca2+ promotes IQ-CaM interactions and increases the amount of IQGAP1-loaded CaM for IQGAP1-mediated signaling. Collectively, we describe IQ- CaM binding in atomistic detail and feature the emergence of Ca2+ as a key modulator of the CaM-IQGAP1 interactions.

关键词： endothelial injury   IQ-GTPase-activating protein   nanoparticle   platelet-derived growth factor receptor   simvastatin  

摘要： Endothelial barrier dysfunction is a critical pathophysiological process of sepsis. Impaired endothelial cell migration is one of the main reasons for endothelial dysfunction. Statins may have a protective effect on endothelial barrier function. However, the effect and mechanism of statins on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction remain unclear. Simvastatin (SV) was loaded in nanostructured lipid carriers to produce SV nanoparticles (SV-NPs). Normal SV and SV-NPs were used to treat human umbilical vein vascular endothelial cells (HUVECs) injured by LPS. Barrier function was evaluated by monitoring cell monolayer permeability and transendothelial electrical resistance, and cell migration ability was measured by a wound healing assay. LY294002 and imatinib were used to inhibit the activity of PI3K/Akt and platelet-derived growth factor receptor (PDGFR) beta. IQ-GTPase-activating protein 1 (IQGAP1) siRNA was used to knockdown endogenous IQGAP1, which was used to verify the role of the PDGFR beta/PI3K/Akt/IQGAP1 pathway in SV/SV-NPs-mediated barrier protection in HUVECs injured by LPS. The results show that SV/SV-NPs promoted the migration and decreased the permeability of HUVECs treated with LPS, and the efficacy of the SV-NPs exceeded that of SV significantly. LY294002, imatinib and IQGAP1 siRNA all suppressed the barrier protection of SV/SV-NPs. SV/SV-NPs promoted the secretion of platelet-derived growth factor-BB (PDGF-BB) and activated the PDGFR beta/PI3K/Akt/IQGAP1 pathway. SV preparations restored endothelial barrier function by restoring endothelial cell migration, which is involved in the regulation of the PDGFR beta/PI3K/Akt/IQGAP1 pathway and PDGF-BB secretion. As an appropriate formulation for restoring endothelial dysfunction, SV-NPs may be more effective than SV.

关键词： 宫颈癌   免疫组织化学   预后  

摘要： 目的观察宫颈癌中IQ结构域GTP酶激活蛋白(IQGAP1)和β连环蛋白(β-catenin)联合表达与宫颈癌的发生、发展相关性,并探讨临床意义。方法收集98例宫颈癌石蜡组织作为观察组,50例癌旁组织为对照组,采用免疫组织化学的方法检测IQGAP1和β-catenin在各组中的表达与宫颈癌临床病理特征及患者预后关系的相关性。结果宫颈癌组织中IQGAP1阳性率76.5%,高于癌旁组织中的表达(28.0%,P=0.001)。β-catenin在宫颈癌组织中的阳性率高于在癌旁组织中的表达(75.5%vs 6.0%,P=0.001)。宫颈癌组织中IQGAP1阳性率与年龄、肿瘤直径无关(P>0.05),与临床分期、是否伴有淋巴结转移、分化程度有关(P=0.001)。β-catenin在宫颈癌中的表达与年龄、肿瘤直径及分化程度无关,与临床分期、是否伴有淋巴结转移有关(P=0.001)。宫颈癌中IQGAP1和β-catenin表达呈正相关(r=0.468,P=0.001)。宫颈癌中IQGAP1和β-catenin共阳性表达的患者生存时间较单阳组、全阴组缩短。结论IQGAP1和β-catenin参与了宫颈癌的发生、发展,并与其高度侵袭性和转移性相关,二者相互协同,共阳性表达提示预后不良。

关键词： Mechanism   SP1   p300   Multiple myeloma   IQGAP1  

摘要： Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and activated Ras/Raf/MEK/ERK pathway. But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain. The mechanism of IQGAP1 overexpression and transcriptional regulation of IQGAP1 gene in myeloma cells was explored in the study. Through bioinformatics analysis and prediction we predicted and screened transcription factor Sp1 as a possible upstream regulator of *** proliferation, cell cycle and downstream ERK1/2 and p-ERK1/2 proteins were detected after siRNA-IQGAP1 was transfected to myeloma cells. The expression of Sp1, p300, IQGAP1, p-ERK1/2 and ERK1/2 were detected after Sp1 and p300 were inhibited or overexpressed respectively. The dual-luciferase reporter system was used to detect the activity of IQGAP1 gene promoter. CHIP was used to detect the binding of the Sp1 and IQGAP1 promoter ***-IP was used to explore the interaction between Sp1 and *** mRNA expression levels of Sp1, p300 and IQGAP1 of the myeloma patients were detected, and the correlation analysis of their mRNA expression levels were carried out. The results showed IQGAP1-siRNA inhibits cell proliferation, cell cycle, IQGAP1 expression and phosphorylation of ERK1/2 protein. Inhibition of Sp1 or p300 down-regulated ERK1/2 and IQGAP1 expression;overexpression of Sp1 or p300 up-regulated ERK1/2 and IQGAP1 expression;Sp1 and p300 had a positive regulation effect on *** expression of Sp1 or p300 significantly increased activity of IQGAP1 gene promoter. The transcription factor Sp1 plays a regulatory role in the IQGAP1 promoter region. There is an interaction between Sp1 and p300 in myeloma cells. The mRNA expression levels of Sp1, IQGAP1 and p300 in MM samples showed a positive correlation. In summary IQGAP1 is required for cell proliferation in MM cells, and the transcription of Sp1/p300 complex regulates expression of IQGAP1 gene.

关键词： HPK1   Autoimmune disease   Cancer metastasis   Aging   IL-17A   PKC theta   IQGAP1   Autophagy   Verteporfin  

摘要： MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKC theta through phosphorylating PKC theta at Ser-538 residue, leading to activation of IKK/NF-kappa B. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients;the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-ROR gamma t complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer;the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. D