更新于：2024-05-01

DOCK8

dedicator of cytokinesis 8

更新于：2024-05-01

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

登录后查看更多信息

100 项与 DOCK8 相关的转化医学

登录后查看更多信息

0 项与 DOCK8 相关的专利（医药）

登录后查看更多信息

297

项与 DOCK8 相关的文献（医药）

2024-02-01·Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

Clinical, immunological, and genetic description of a Mexican cohort of patients with DOCK8 deficiency.

Article

作者: Eduardo Liquidano-Perez ; Gibert Maza-Ramos ; Bethy Alexandra Perez Arias ; Saul Oswaldo Lugo Reyes ; Tania Barragan Arevalo ; Sara Alejandra Solorzano-Morales ; Edna Venegas Montoya ; Aidé Tamara Staines-Boone ; Rogelio Guzmán Cotaya ; Satoshi Okada ; Capucine Picard ; Etienne Patin ; Nideshda Ramirez-Uribe ; Juan Carlos Bustamante-Ogando ; Selma Cecilia Scheffler-Mendoza ; Marco Antonio Yamazaki-Nakashimada ; Marimar Saez-de-Ocariz ; Sara Elva Espinosa Padilla ; Maria Edith Gonzalez-Serrano

PURPOSE:

We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children.

METHODS:

Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method.

RESULTS:

We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis.

CONCLUSION:

DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.

2024-01-05·The Journal of allergy and clinical immunology

Treg cell dysfunction and cutaneous exposure to S. aureus underlie eczema in DOCK8 deficiency.

Article

作者: Hazel Wilkie ; Mrinmoy Das ; Tyler Pelovitz ; Wayne Bainter ; Brian Woods ; Mohammed Alasharee ; Ali Sobh ; Safa Baris ; Sevgi Bilgic Eltan ; Waleed Al-Herz ; Mohamed-Ridha Barbouche ; Imen Ben-Mustapha ; Meriem Ben-Ali ; Mohamed T H Sallam ; Amany Awad ; Sohilla Lotfy ; Aisha El Marsafy ; Moushira Ezzelarab ; Michael Farrar ; Brigitta A R Schmidt ; Monali NandyMazumdar ; Emma Guttman-Yassky ; Anthony Sheets ; Katie Maria Vidic ; George Murphy ; Patrick M Schlievert ; Janet Chou ; Juan Manuel Leyva-Castillo ; Erin Janssen ; Maheshwor Timilshina ; Raif S Geha

BACKGROUND:

DOCK8-deficient patients have severe eczema, elevated IgE and eosinophilia, features of Atopic Dermatitis (AD).

OBJECTIVE:

To understand the mechanisms of eczema in DOCK8 deficiency.

METHODS:

Skin biopsies were characterized for histology, immuno-fluorescence microscopy, and gene expression. Skin barrier function was measured by trans-epidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous (EC) sensitization with ovalbumin (OVA) or cutaneous application of S. aureus.

RESULTS:

Skin lesions of DOCK8-deficient patients exhibited type-2 inflammation and the patients' skin was colonized by S. aureus, like in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8^-/- mice exhibited reduced numbers of cutaneous T regulatory cells (Tregs) and a normal skin barrier. Dock8^-/- mice and mice with an inducible Dock8 deletion in Tregs exhibited increased allergic skin inflammation following EC sensitization with OVA. DOCK8 was shown to be important for Treg stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Tregs (iTregs). Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific iTregs suppressed allergic inflammation in OVA-sensitized skin of Dock8^-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels following topical exposure to S. aureus. Both were attenuated following adoptive transfer of WT but not DOCK8 deficient Tregs CONCLUSION: Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to S. aureus to drive eczema in DOCK8 deficiency.

2024-01-05·Archives of pathology & laboratory medicine

Synchronous Epidermodysplasia Verruciformis and Intraepithelial Lesion of the Vulva Is Caused by Coinfection With Alpha-Human Papillomavirus and Beta-Human Papillomavirus Genotypes and Facilitated by Mutations in Cell-Mediated Immunity Genes.

Article

作者: Renan Ribeiro E Ribeiro ; C James Sung ; M Ruhul Quddus

CONTEXT.—:

There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature.

OBJECTIVES.—:

To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with α and β human papillomavirus (α-HPV and β-HPV) genotypes, and describe relevant underlying genetic mutations.

DESIGN.—:

Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed.

RESULTS.—:

Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both α-HPVs and β-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found.

CONCLUSIONS.—:

We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with α-HPV and β-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status.

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