DOCK8 is a Novel Regulator of Lysosome-Mediated Pancreatic Cancer Invasion
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE185335 | GEO | 2023/08/03
REPOSITORIES: GEO
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Project description:Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor progression and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) DOCK8 on lysosomes. Surprisingly, we found that DOCK8 is aberrantly expressed in a subset of PDAC where it promotes cell invasion and proliferation. Further, DOCK8 associates with lysosomes and regulates lysosomal morphology and motility. DOCK8 promotes actin polymerization at the surface of lysosomes, while increasing the levels and proteolytic activity of the lysosomal protease cathepsin B. Depletion of DOCK8 significantly reduces extracellular matrix degradation and impairs the invasive capacity of PDAC cells. Further, CRISPR-based knockout of DOCK8 dramatically reduces tumor size and metastasis in vivo. Together, these findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation, tumor progression, and metastasis.
2023-01-10 | MSV000091036 | MassIVE
Project description:Analysis of DOCK8 deficient animals revealed a key role for this protein the survival and maintenance of natural killer T cells. This work lead to the identification of genes regulated by the guanine exchange factor, DOCK8. Total RNA was extracted from 3 biological replicates of thymic, DOCK8 deficient NKT cells and compared using an Illumina microarray to WT NKT cells.
2013-09-01 | E-GEOD-44814 | biostudies-arrayexpress
Project description:Analysis of DOCK8 deficient animals revealed a key role for this protein the survival and maintenance of natural killer T cells. This work lead to the identification of genes regulated by the guanine exchange factor, DOCK8.
2013-09-01 | GSE44814 | GEO
Project description:Patients deficient in the guanine nucleotide exchange factor DOCK8 have decreased numbers and impaired in vitro function of T regulatory (Treg) cells and make autoantibodies, but seldom develop autoimmunity. We show that similarly, Dock8-/- mice have decreased numbers and impaired in vitrofunction of Treg cells, but do not develop autoimmunity. In contrast, mice with selective DOCK8 deficiency in Treg cells develop lymphoproliferation, autoantibodies, and gastrointestinal inflammation, despite normal percentage and in vitro function of Treg cells, suggesting that deficient T effector cell function might protect DOCK8 deficient patients from autoimmunity. We demonstrate that DOCK8 associates with STAT5 and is important for IL-2 driven STAT5 phosphorylation in Treg cells. DOCK8 localizes within the lamellar actin ring of the Treg cell immune synapse (IS). Dock8-/- Treg cells have abnormal TCR-driven actin dynamics, decreased adhesiveness, altered gene expression profile, an unstable IS with decreased recruitment of signaling molecules, and impaired transendocytosis of the co-stimulatory molecule CD86. These data suggest that DOCK8 enforces immunological tolerance by promoting IL-2 signaling, TCR-driven actin dynamics, and the IS in Treg cells.
2017-08-12 | GSE102577 | GEO
Project description:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease of unknown cause. We show here that a novel T follicular helper cell type expressing the guanine nucleotide exchange factor DOCK8 on the cell surface causes SLE. These cells, which we have designated autoantibody-inducing CD4 T (aiCD4 T) cells, are generated after resuscitation from anergy following strong TCR stimulation by antigen. When mice normally not prone to autoimmune disease were repeatedly immunized with an antigen such as OVA, they generated DOCK8+ CD4 T cells. These DOCK8+ CD4 T cells, in vivo and also upon transfer to naïve mice, induced a variety of autoantibodies and lesions characteristic of SLE. TCR repertoire analyses showed that a substantial number of novel TCR repertoires were generated in the DOCK8+ CD4 T cells, which induced novel autoantibodies upon transfer to naïve mice. DOCK8+ CD4 T cells are localized in splenic red pulp, the space immunoreactive against a variety of antigens, and specifically increased in the peripheral blood of SLE patients in association with disease activity. Anti-DOCK8 antibody treatment ameliorated the lesions induced by DOCK8+ CD4 T cells and in lupus model (NZB x W) F1 mice. Thus, when CD4 T cells are overstimulated by an external disturbance, i.e., repeatedly stimulated with antigen, to levels that surpass the system’s self-organized criticality, these cells express DOCK8 on the cell surface and acquire autoreactivity via TCR re-revision at the periphery. These DOCK8+ CD4 T cells subsequently induce a variety of autoantibodies and SLE.
2020-10-09 | GSE159240 | GEO
Project description:Rab GTPases are primarly involved in trafficking processes. Rinl belongs to the Ras-interaction/interference (Rin) proteins and is a guanine nucleotide exchange factor (GEF) for Rab5a and Rab22. By transcriptome analysis of naïve and effector CD4+ T cells we identify Rinl-regulated pathways in CD4+ T cells.
2023-08-28 | GSE235805 | GEO
Project description:Background: DOCK8 deficiency is an autosomal recessive form of hyperimmunoglobulinemia E syndrome (HIES). Severe atopic dermatitis (AD) shares with DOCK8 deficiency some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. The deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Despite identified metabolomics and cytokine biomarkers, novel proteomics biomarkers need to be identified, as the connecting networks are critical to our understanding of this disease. Hence we performed serum proteomics profiling using LC-MSE SynaptG2. Method: Label-free untargeted proteomics analysis was used to identify potentially reliable, sensitive, and specific protein biomarkers in serum collected from DOCK8 (n=10), AD (n=9) patients, which were compared to ctrls (n=5). Results: From a total of 275 quantifiable proteins, binary comparisons between AD vs. Ctrl, DOCK8 vs. Ctrl, and DOCK8 vs. AD revealed 109, 105 and 85 dysregulated proteins, respectively. 24 among 85 proteins were specific potential biomarkers among the DOCK8 and AD groups. The sensitivity and specificity of few proteins like Claspin, Immunoglobulin kappa and heavy, complement components as potential biomarkers to distinguish between DOCK8 and AD patients were evaluated using the receiver operating characteristic curve. DOCK8 deficiency and AD groups' profiling revealed a shared role of ERK1/2 among the commonly dysregulated proteins. Conclusion: In this study, we have identified potential proteomics biomarkers and profile to distinguish between DOCK8 and AD, with possible diagnostic and therapeutic applications to help create effective interventions for managing these diseases. Further studies to confirm these associations in prospective cohorts are warranted.
2022-05-17 | PXD029052 | Pride
Project description:Mutations in the DOCK8 gene cause an autosomal recessive form of hyper-immunoglobulin E syndrome, characterised by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. Here, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8 deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8 deficient patients had attenuated production of IFNγ and TNFα upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell driven immunity.
2017-09-15 | GSE101467 | GEO
Project description:To examine the genes involved in IL-31-evoked itch sensation, we employed microarray expression profiling and found that 698 genes were expressed at higher levels in the DRG neurons of Dock8–/– (tcr)AND Tg mice (high IL-31 level) than those of Dock8+/– controls (low IL-31 level).
2019-08-09 | GSE118986 | GEO
Project description:To examine the effect of DOCK8 deficiency on helper T cell differentiation, we employed microarray expression profiling and found that 850 genes were expressed at higher levels in Dock8–/– AND CD4+ T cells than Dock8+/– controls after antigen stimulation.
2016-12-01 | GSE75686 | GEO