更新于：2024-11-01

DOCK8

更新于：2024-11-01

基本信息

别名

dedicator of cytokinesis 8、Dedicator of cytokinesis protein 8、DOCK8

+ [4]

简介

Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PubMed:28028151, PubMed:22461490). During immune responses, required for interstitial dendritic cell (DC) migration by locally activating CDC42 at the leading edge membrane of DC (By similarity). Required for CD4(+) T-cell migration in response to chemokine stimulation by promoting CDC42 activation at T cell leading edge membrane (PubMed:28028151). Is involved in NK cell cytotoxicity by controlling polarization of microtubule-organizing center (MTOC), and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PubMed:25762780).

关联

项与 DOCK8 相关的药物

MR-022

靶点

DOCK8 x KRT8

作用机制

DOCK8 inhibitors [+1]

在研机构-

原研机构

Centre Léon Bérard Lyon et Rhône-Alpes

在研适应症-

非在研适应症

结直肠癌

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DOCK8 相关的临床结果

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100 项与 DOCK8 相关的转化医学

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0 项与 DOCK8 相关的专利（医药）

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330

项与 DOCK8 相关的文献（医药）

2024-12-01·Cellular and Molecular Neurobiology

Analysis and Regulatory Mechanisms of Platelet-Related Genes in Patients with Ischemic Stroke

Article

作者: Shu, Yuanlu ; Li, Yuan ; Ni, Ruihan ; Yu, Kun ; Chu, Lan

It was found that ischemic stroke (IS) was associated with abnormal platelet activity and thrombosis. However, the potential significance of platelet-related genes (PRGs) in IS still needs to be more thorough. This study extracted IS-related transcriptome datasets from the Gene Expression Omnibus (GEO) database. The target genes were obtained by intersecting the differentially expressed genes (DEGs), the module genes related to IS, and PRGs, where the key genes of IS were screened by two machine learning algorithms. The key genes-based diagnostic model was constructed. Gene set enrichment analysis (GSEA) and the immune microenvironment analyses were analyzed targeting key genes in IS. The co-expression, TF-mRNA, and competitive endogenous RNAs (ceRNA) regulatory networks were constructed to reveal the potential regulation of key genes. Potential drugs targeting key genes were predicted as well. Totals of eight target genes were obtained and were associated with immune-related functions. Four platelet-related key genes were acquired, which were related to immunity and energy metabolism. The abnormal expressions of DOCK8, GIMAP5, ICOS were determined by the quantitative real-time polymerase chain reaction (qRT-PCR), and the significant correlations among these key genes were identified. Notably, hsa-miR-17-3p, hsa-miR-3158-3p, hsa-miR-423-3p, and hsa-miR-193a-8p could regulate all key genes at the same time. In addition, Caffeine, Carboplatin, and Vopratelimab were the targeted drugs of these key genes. This study identified four platelet-related key genes of IS, which might help to deepen the understanding of the role of platelet-related genes in the molecular mechanism of IS.

2024-11-01·Journal of Clinical Immunology

A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries

Review

作者: Sullivan, Anna ; O'Young, Patrick ; Zhang, Qian ; Hobbs, Matthew ; Huynh, Aimee ; Wainwright, Luke H ; Hsiao, Kuang-Chih ; Pinzon-Charry, Alberto ; Gray, Paul E ; Bastard, Paul ; Guerin, Antoine ; Casanova, Jean-Laurent ; Higgins, Megan ; Noon, Fallon ; Ma, Cindy S ; McManus, Sam ; Rao, Geetha ; Mackie, Joseph ; Wong, Melanie ; Hollway, Georgina ; Pathmanandavel, Karrnan ; Enthoven, Karen ; Tangye, Stuart G ; Mina, Erika Della

AbstractAdvanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.

2024-11-01·Clinical Immunology

DOCK8 deficiency due to a deep intronic variant in two kindreds with hyper-IgE syndrome

Article

作者: Keles, Sevgi ; Gungor, Hatice Eke ; Cansever, Murat ; Wang, Muyun ; Can, Salim ; Baris, Safa ; Schmitz-Abe, Klaus ; Chatila, Talal A. ; Eke Gungor, Hatice ; Chatila, Talal A ; Benamar, Mehdi ; Oktelik, Fatma Betul ; Karakoc-Aydiner, Elif

Dedicator of cytokinesis 8 (DOCK8) deficiency underlies the majority of cases of patients with autosomal recessive form of the hyper-immunoglobulin E syndrome (HIES). Most DOCK8 mutations involve deletions and splice junction mutations that abrogate protein expression. However, a few patients whose presentation is reminiscent of DOCK8 deficiency have no identifiable mutations. Using Whole Exome Sequencing (WES), we identified a deep intronic homozygous DOCK8 variant located in intron 36 (c.4626 + 76 A > G) in two unrelated patients with features of HIES that resulted in an in-frame 75 base pair intronic sequence insertion in DOCK8 cDNA, resulting in a premature stop codon (p.S1542ins6Ter). This variant resulted in variable decrease in DOCK8 expression that was associated with impaired T cell receptor-triggered actin polymerization, decreased IL-6-induced STAT3 phosphorylation, reduced expression of the Th17 cell markers CCR6 and IL-17, and higher frequencies of GATA3⁺ T cells indicative of Th2 skewing. Our approach extends the reach of WES in identifying disease-related intronic variants. It highlights the role of non-coding mutations in immunodeficiency disorders, including DOCK8 deficiency, and emphasizes the need to explore these mutations in unexplained inborn errors of immunity.

项与 DOCK8 相关的新闻（医药）

2023-12-28

·生物谷

Cell Rep：科学家揭示胰腺癌扩散的新型分子机制

来自梅奥诊所等机构的科学家们通过对胰腺癌进一步研究揭示了其发生转移背后的分子机制，研究人员识别出了一种特殊的细胞信号蛋白，其能驱动胰腺癌细胞的生长，这或许有望作为一种潜在的治疗性靶点。癌症如何扩散或发生转移对于癌症研究人员和患者而言一直是一个大问题，近日，一篇发表在国际杂志Cell Reports上题为“Ectopic expression of DOCK8 regulates lysosome-mediated pancreatic tumor cell invasion”的研究报告中，来自梅奥诊所等机构的科学家们通过对胰腺癌进一步研究揭示了其发生转移背后的分子机制，研究人员识别出了一种特殊的细胞信号蛋白，其能驱动胰腺癌细胞的生长，这或许有望作为一种潜在的治疗性靶点。研究者Gina Razidlo说道，我们的最终目标是找到引发转移的诱因并及时对其进行阻断，同时结合减少肿瘤生长的疗法，我们就有望改善患者的治疗结果。肿瘤往往会生长在营养匮乏的环境中，因此癌细胞就必须重新修饰其细胞代谢从而来满足其能量需求。癌细胞劫持代谢通路的其中一种方式就是通过溶酶体（lysosomes），其就好像细胞的胃部一样发挥功能，其中充满了消化酶，溶酶体能分解促进细胞生长的蛋白质、脂质和营养物质，此前有研究表明，溶酶体活性的扩增或许就是多种癌症发生的标志。这一认识或许就促使研究者Razidlo等人开始密切关注因癌基因KRAS突变所驱动的胰腺癌细胞中的溶酶体的特征，文章中，研究人员比较了表达癌基因KRAS的胰腺癌细胞所表达的溶酶体与携带健康KRAS的细胞所表达的溶酶体的差异，旨在阐明其二者之间的差异，在研究人员发现的胰腺癌细胞溶酶体表面发生改变的52种蛋白中，有一种名为胞质分裂贡献体8（DOCK8，dedicator of cytokinesis 8）的蛋白质表现非常突出。科学家揭示胰腺癌扩散的新型分子机制。图片来源：Cell Reports (2023). DOI:10.1016/j.celrep.2023.113042 DOCK8能产生入侵的突起，就好像小手臂一样能穿过细胞并改变细胞的结构，同时还能降解其周围的环境，DOCK8通常存在于健康的免疫细胞中，其能帮助细胞导航并挤压致密组织，促进细胞对感染产生反应并抵御感染，让研究人员意外的是，他们发现，DOCK8竟然也存在于胰腺癌细胞的溶酶体上。那么癌细胞的入侵和扩散如何类似于DOCK8帮助免疫细胞浸润到组织中，研究人员进一步研究观察了胰腺癌细胞的图像和视频，结果发现，DOCK8能利用溶酶体来分解癌细胞周围的细胞外环境，并帮助其扩散。为了证实这种蛋白能参与到肿瘤进展过程中，研究人员利用基因编辑工具CRISPR消除了胰腺癌细胞中的DOCK8，结果在临床前模型中发现，剔除了DOCK8的溶酶体移动地较慢，肿瘤生长和转移也会发生减缓，随后他们进一步研究发现，DOCK8存在于大约20%的胰腺癌患者机体的细胞中。如今研究人员发现，DOCK8能调节胰腺癌细胞的转移过程，其或能作为一种潜在的治疗性靶点来帮助预防或停止胰腺癌的转移。综上，本文研究结果表明，DOCK8的异位表达或许能作为胰腺癌细胞中KRAS驱动的溶酶体调节和侵袭的关键驱动因素。（生物谷Bioon.com）原始出处： Omar L. Gutierrez-Ruiz，Katherine M. Johnson，Eugene W. Krueger, et al. Ectopic expression of DOCK8 regulates lysosome-mediated pancreatic tumor cell invasion, Cell Reports (2023). DOI:10.1016/j.celrep.2023.113042