| 2004 |
DOCK8 was identified in a yeast two-hybrid screen as a Cdc42-interacting protein with similarity to DOCK180. Immunofluorescence showed that HA-tagged and endogenous DOCK8 localizes to cell edges at sites of lamellipodia formation. Transfection of a C-terminal fragment caused formation of vesicular structures containing filamentous actin, implicating DOCK8 in regulation of filamentous actin organization. |
Yeast two-hybrid screen, immunofluorescence, transient transfection |
FEBS letters |
Medium |
15304341
|
| 2009 |
DOCK8 mutations in mice abolish formation of marginal zone B cells and germinal center B cell persistence, preventing affinity maturation. DOCK8 mutations specifically disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. |
Mouse genetic screen (ENU mutagenesis), loss-of-function mouse model, immunological synapse imaging, flow cytometry |
Nature immunology |
High |
19898472
|
| 2012 |
DOCK8 is a Cdc42-specific guanine nucleotide exchange factor (GEF) required for interstitial dendritic cell migration. DOCK8-deficient DCs failed to accumulate in lymph node parenchyma, could not crawl in 3D fibrillar networks or transmigrate through the subcapsular sinus floor, but migrated normally on 2D surfaces. This function depended on the DHR-2 domain mediating Cdc42 activation. Spatial Cdc42 activation at the leading edge membrane (not global Cdc42 activity) was impaired in DOCK8-deficient DCs. |
DOCK8 knockout mice, 2D and 3D migration assays, domain mutant rescue experiments, Cdc42 activity assays (global and spatially resolved) |
Blood |
High |
22461490
|
| 2012 |
DOCK8 functions as an adaptor in TLR9-MyD88 signaling in B cells. DOCK8 constitutively associates with MyD88 and the tyrosine kinase Pyk2. After TLR9 ligation, DOCK8 is tyrosine-phosphorylated by Pyk2, then binds the Src-family kinase Lyn, linking TLR9 to a Src-Syk-STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. TLR9-driven B cell activation was impaired in DOCK8-deficient patients, while CD40-driven activation was not. |
Co-immunoprecipitation, phosphorylation assays, DOCK8-deficient patient B cells, selective functional assays (TLR9 vs CD40 stimulation) |
Nature immunology |
High |
22581261
|
| 2011 |
DOCK8 is required cell-autonomously for peripheral CD8 T cell survival and function. DOCK8 mutation diminished naive CD8 T cell abundance, shortened naive CD8 T cell lifespan, impaired LFA-1 synaptic polarization upon DC encounter, delayed first cell division, and greatly reduced memory cell persistence after infection. These defects were established as postthymic and cell-autonomous in both mice and humans. |
DOCK8-mutant mice and human patient cells, cell transfer experiments (cell autonomy), in vivo influenza infection, LFA-1 polarization imaging, lifespan analysis |
The Journal of experimental medicine |
High |
22006977
|
| 2011 |
DOCK8 deficiency in mice causes T cell lymphopenia with increased T cell turnover and decreased survival. Egress of mature CD4+ thymocytes is reduced with increased migration toward CXCL12. DOCK8 is limiting specifically for the survival of CD8+ memory T cells after viral infection, not for the primary CD8 response. |
DOCK8-deficient mouse analysis, flow cytometry, chemokine migration assays, influenza infection model |
European journal of immunology |
High |
21969276
|
| 2014 |
DOCK8, through CDC42 and p21-activated kinase (PAK), coordinates cytoskeletal structures during lymphocyte migration through confined, collagen-dense spaces. DOCK8-deficient T and NK cells develop cell shape and nuclear deformation abnormalities leading to cytothripsis (migration-induced catastrophic cell death) without impairing chemotaxis. This prevents generation of long-lived skin-resident memory CD8 T cells and impairs herpesvirus skin infection control. |
DOCK8-deficient patient and mouse cells, live imaging of lymphocyte migration through confined spaces, collagen matrix migration assays, in vivo herpesvirus skin infection model, resident memory T cell quantification |
The Journal of experimental medicine |
High |
25422492
|
| 2016 |
DOCK8 bridges WASp-interacting protein (WIP) to WASp and actin in T cells, forming a DOCK8-WIP-WASp complex. The GEF activity of DOCK8 is essential for subcortical actin cytoskeleton integrity, TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes — all of which also depend on WASp, placing DOCK8 and WASp in the same TCR-to-actin signaling pathway. |
Co-immunoprecipitation, DOCK8-deficient patient T cells, GEF-dead mutant rescue, actin assembly assays, immune synapse imaging, transendothelial migration assay, in vivo lymph node homing |
The Journal of clinical investigation |
High |
27599296
|
| 2013 |
DOCK8 deficiency impairs NKT cell development, specifically affecting formation and survival of long-lived, differentiated NK1.1+ NKT cells expressing CD103 in the thymus. DOCK8-deficient NKT cells in the liver express reduced levels of the prosurvival factor Bcl-2 and LFA-1. Initial NKT cell response to antigen is intact but ongoing proliferative and cytokine responses are impaired. |
DOCK8-deficient mouse model, flow cytometry (thymic and hepatic NKT cell subsets), Bcl-2 expression analysis, antigen response assays, validation in DOCK8-deficient humans |
Blood |
High |
23929855
|
| 2015 |
DOCK8 is absolutely required for dendritic cell migration during immune responses. Coincidental loss of DOCK8 in NLRP10-deficient mice (due to an unexpected Dock8 mutation) was shown by whole-exome sequencing and confirmed by targeted deletion: isolated DOCK8 deficiency recapitulates the DC migration defect. C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. |
Proteomic screen, whole-exome sequencing, targeted Dock8 deletion, in vivo DC migration assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25713392
|
| 2016 |
DOCK8 is a Cdc42-specific GEF required for macrophage migration in a 2D setting. The GEF activity of DOCK8 (not merely protein scaffolding) is required for macrophage migration. DOCK8 associates with LRAP35a, an adaptor that binds the Cdc42 effector MRCK, and facilitates MRCK phosphorylation of myosin II regulatory light chain. Disrupting the DOCK8-LRAP35a interaction in WT macrophages recapitulates the DOCK8-deficient migration defect. |
DOCK8-deficient macrophages, GEF-activity rescue experiments, co-immunoprecipitation, LRAP35a interaction-disruption experiments, myosin RLC phosphorylation assays |
The Journal of biological chemistry |
High |
28028174
|
| 2017 |
LRCH1 competes with Cdc42 for interaction with DOCK8, restraining T cell migration. In response to chemokine stimulation, PKCα phosphorylates DOCK8 at three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration. Point mutations at DOCK8 serine sites block chemokine- and PKCα-induced T cell migration. |
Two screening systems (protein interaction screens), competition binding assays, PKCα phosphorylation assays, site-directed mutagenesis of DOCK8 serine sites, Dock8-mutant and Lrch1-transgenic/knockout mouse EAE models |
The Journal of experimental medicine |
High |
28028151
|
| 2017 |
DOCK8 is a negative regulator of nuclear translocation of the transcription factor EPAS1 in CD4+ T cells, acting as an adaptor. In DOCK8-deficient CD4+ T cells, EPAS1 translocates to the nucleus and drives IL-31 expression by activating the Il31 promoter in collaboration with SP1 (not ARNT). IL-31 induction drives atopic skin inflammation. Conditional deletion of EPAS1 in CD4+ T cells abrogates skin disease in DOCK8-deficient mice. |
DOCK8-deficient mouse model, conditional EPAS1 deletion, IL-31 production assays, promoter activation assays, nuclear translocation imaging |
Nature communications |
High |
28067314
|
| 2017 |
DOCK8 regulates Treg fitness and function via IL-2 signaling in a STAT5-dependent manner. Treg-specific DOCK8 deletion caused spontaneous multiorgan inflammation. DOCK8-deficient Tregs are defective in competitive fitness and in vivo suppressive function. DOCK8 controls IL-2-driven STAT5 phosphorylation in Tregs. |
Conditional Treg-specific DOCK8 knockout mice, STAT5 phosphorylation assays, competitive fitness assays, in vivo suppression assays |
JCI insight |
High |
28978795
|
| 2017 |
DOCK8 associates with STAT5 and is required for IL-2-driven STAT5 phosphorylation in Tregs. DOCK8 localizes within the lamellar actin ring of the Treg immune synapse (IS). DOCK8-deficient Tregs have abnormal TCR-driven actin dynamics, decreased adhesiveness, an unstable IS with decreased recruitment of signaling molecules, and impaired transendocytosis of CD86. Mice with selective DOCK8 deficiency in Tregs develop lymphoproliferation, autoantibodies, and gastrointestinal inflammation. |
DOCK8-Treg conditional knockout mice, Co-IP (DOCK8-STAT5 association), STAT5 phosphorylation assays, IS imaging, actin dynamics assays, CD86 transendocytosis assay |
JCI insight |
High |
28978806
|
| 2017 |
DOCK8 regulates NK cell cytotoxicity and cytokine production via Src family kinase (particularly Lck) activation downstream of target cell engagement or NKp30 ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation. PMA/ionomycin rescued cytokine production in DOCK8-deficient NK cells, indicating the defect is proximal to receptor ligation. |
DOCK8 knockdown in human NK cells, DOCK8-deficient patient NK cells, cytokine production assays, Src/Lck kinase activation assays, PMA/ionomycin rescue experiments |
Journal of immunology |
High |
28794229
|
| 2016 |
DOCK8 interacts with Nck1 via its unique N-terminal proline-rich motif binding the SH3 domain of Nck1 to promote PDGF-induced Schwann cell precursor migration. Knockdown of Dock8 or Nck1 markedly decreased PDGF-induced cell migration and Rho GTPase activation. Reintroduction of a proline-rich motif mutant of Dock8 failed to restore migration, while wild-type Dock8 restored it. |
siRNA knockdown, Co-IP/pulldown (proline-rich motif – SH3 interaction), domain mutant rescue, cell migration assays, Rho GTPase activation assays |
Biochemistry and biophysics reports |
Medium |
28955869
|
| 2018 |
DOCK8 regulates BCR signaling by controlling cd19 transcription via WASP. DOCK8-deficient B cells show reduced total WASP protein and reduced WASP activation; since WASP positively regulates CD19 transcription, reduced DOCK8 leads to decreased CD19 and impaired upstream BCR signaling (pCD19 and pBtk). DOCK8 deficiency disrupts early activation of memory B cells, including reduced BCR clustering, B cell spreading, and signalosome recruitment. |
DOCK8 knockout mouse model, DOCK8-deficient patient PBMCs, confocal microscopy, TIRF microscopy, BCR signaling assays (pCD19, pBtk), WASP expression and activation assays |
Blood advances |
High |
29472447
|
| 2019 |
DOCK8 is expressed in microglia and its expression increases during neuroinflammation. DOCK8-deficient mice exhibit reduced microglial migration through retinal layers in a model of MS/optic neuritis, and reduced severity of neuroinflammation. In a glaucoma model, DOCK8-deficient mice show impaired microglial phagocytosis of retinal ganglion cells. |
DOCK8-deficient mice, retinal immunofluorescence, disease models (optic neuritis and glaucoma), microglial migration and phagocytosis assays |
The Journal of biological chemistry |
Medium |
31337702
|
| 2020 |
DOCK8-deficient CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing IL-1β. This IL-1β drives GM-CSF production by CD4+ T cells, resulting in a TH2 cell bias. Blocking IL-1β, GM-CSF, or caspase activation eliminated the type-2 skew in Dock8-/- mice. |
Dock8-/- mice, Cryptococcus neoformans pulmonary infection model, IL-1β and GM-CSF blocking experiments, caspase inhibition, apoptotic cell transfer experiments |
Nature immunology |
High |
33020661
|
| 2020 |
DOCK8 is essential for LFA-1-dependent positioning of T follicular helper (Tfh) cells in germinal centers. Mice with T cell-selective DOCK8 deficiency had impaired IgG responses to T cell-dependent antigens, decreased GC size, and reduced GC B cells, despite normal Tfh numbers. Migration of DOCK8-deficient T cells into GCs was defective. Following TCR/CD3 ligation, DOCK8-deficient T cells showed impaired LFA-1 activation and reduced ICAM-1 binding. |
T cell-selective DOCK8 knockout mice, in vivo GC analysis, DOCK8-deficient T cell-B cell co-culture, LFA-1 activation assays, ICAM-1 binding assays, intravital imaging |
JCI insight |
High |
32573493
|
| 2021 |
The DHR-1 domain of DOCK8 binds specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and is required for DOCK8 recruitment to the plasma membrane. Crystal structure and biochemical analyses revealed a C2 domain-like core with a pocket containing three basic residues for stereospecific phosphoinositide recognition. Substitution of K576 and R581 with alanine abolished PI(4,5)P2 binding in vitro, ablated Cdc42 activation, and impaired leukocyte migration in 3D collagen gels. Dendritic cells carrying the mutation exhibited defective interstitial migration in vivo. |
Crystal structure of DHR-1 domain, in vitro phosphoinositide binding assays, site-directed mutagenesis (K576A/R581A), 3D migration assays, in vivo DC migration assay |
Life science alliance |
High |
33574036
|
| 2021 |
DOCK8 deficiency in Tregs increases susceptibility to allergic skin inflammation and eczema. DOCK8 is important for Treg stability at sites of allergic inflammation and for generation, survival, and suppressive activity of inducible Tregs. Adoptive transfer of WT but not DOCK8-deficient OVA-specific inducible Tregs suppressed allergic inflammation in sensitized Dock8-/- mice. Cutaneous Staphylococcus aureus exposure in DOCK8-deficient mice caused severe allergic inflammation and elevated IgE attenuated by WT Treg transfer. |
Dock8-/- mice, Treg-specific inducible Dock8 deletion, epicutaneous OVA sensitization model, S. aureus topical exposure model, adoptive Treg transfer, skin biopsy histology and gene expression |
The Journal of allergy and clinical immunology |
High |
38185418
|
| 2014 |
DOCK8 deficiency impairs RORγt+ ILC survival and function. DOCK8-deficient RORγt+ ILCs are less responsive to IL-7-mediated signaling, more prone to apoptosis, produce less IL-22, and have defective IL-23-mediated STAT3 phosphorylation. DOCK8 deficiency leads to susceptibility to Citrobacter rodentium infection associated with impaired antimicrobial peptide induction in the colon. |
Dock8-deficient mice, Citrobacter rodentium infection model, RNA-seq, IL-7 signaling assays, STAT3 phosphorylation assays, apoptosis assays |
Nature communications |
High |
25091235
|
| 2015 |
DOCK8 deficiency in CD147-overexpressing hepatocellular carcinoma cells: CD147 upregulates pY416-Src via FAK, Src promotes STAT3 phosphorylation, STAT3 facilitates DOCK8 transcription enhancing DOCK8 expression, and DOCK8 acts as a GEF for Rac1 to drive mesenchymal-type cell movement. |
Confocal microscopy, Rac1 activity assay, Src/STAT3 phosphorylation assays, DOCK8 overexpression/knockdown, transcription assays |
Oncotarget |
Medium |
25428919
|
| 2021 |
DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of ILC2s. Intestinal ILC2 expansion occurs when DOCK8 expression is deleted in hematopoietic cells. Mice carrying mutations in the catalytic center of DOCK8 (DOCK8VAGR, failing to activate Cdc42) also show intestinal ILC2 expansion, indicating that DOCK8 negatively regulates intestinal ILC2s via Cdc42 activation. |
Dock8-/- mice, hematopoietic-specific Dock8 deletion, DOCK8 catalytic mutant (VAGR) mice, CyTOF high-dimensional phenotyping, ILC2 quantification |
Biochemical and biophysical research communications |
High |
33940384
|
| 2023 |
DOCK8 is required for the metabolic fitness and long-term survival of IgA+ plasma cells in the gut lamina propria. B cell-intrinsic DOCK8 is required for maintenance of antigen-specific IgA-secreting plasma cells. DOCK8 deficiency is not required for early B cell activation, migration, or IgA class switching. An interactome screen revealed DOCK8 protein partners involved in metabolism and apoptosis; Dock8-deficient IgA+ B cells have impaired cellular respiration and fail to engage glycolysis appropriately. |
Dock8-deficient mice, B cell-specific deletion, immunization and infection models, unbiased interactome screen (mass spectrometry), cellular respiration and glycolysis assays (Seahorse) |
Mucosal immunology |
High |
38159726
|
| 2025 |
DOCK8-deficient activated T cells lack a central pool of F-actin that is present in wild-type murine and human T cells. This central actin pool is mechanosensitive and forms only under confinement. Loss of the central actin pool in Dock8-deficient T cells results in greater nuclear deformation, DNA damage accrual, and premature cell senescence. Mst1 kinase was identified as a necessary component of this mechanosensitive pathway alongside DOCK8. |
Dock8 knockout mice, human patient T cells, confocal and live imaging of F-actin under confinement, DNA damage assays, cell senescence assays, Mst1 genetic analysis |
Science immunology |
High |
40570086
|
| 2016 |
DOCK8 interacts with septin 7 and integrin-linked kinase (ILK) in primary blood-derived lymphocytes as identified by interaction proteomics. In equine recurrent uveitis (autoimmune disease model), DOCK8 expression and its interaction network are significantly altered. |
Interaction proteomics (Co-IP + mass spectrometry), flow cytometry for expression, equine autoimmune uveitis model |
Scientific reports |
Low |
30120291
|
| 2020 |
DOCK8 expression in Tregs limits contact hypersensitivity by promoting Treg stability and fitness in inflamed skin. Lack of DOCK8 in Tregs resulted in their acquisition of a pathogenic FOXP3+T-bet+IFNγ+ phenotype at CHS sites and promoted conversion into ex-Tregs. Transfer of Dock8-/- Tregs increased the CHS response of WT recipients, while WT Tregs suppressed it. |
Dock8-/- mice, T cell- and Treg-specific DOCK8 knockout, oxazolone CHS model, oral tolerance assays, Treg transfer experiments, flow cytometry phenotyping |
The Journal of investigative dermatology |
High |
33171169
|
| 2024 |
DOCK8 mutation (exon 45, c.5846C>A) generated by CRISPR/Cas9 in mice inhibits splenic MZ and GC B cell development and cripples BCR signaling. The reduced BCR signaling was related to decreased B cell spreading, BCR clustering, and signalosomes, mediated by inhibited activation of WASP. Additionally, DOCK8 mutation led to increased c-Myc expression in B cells, enhancing glycolysis. |
CRISPR/Cas9 knock-in mouse model (patient-derived point mutation), flow cytometry, BCR signaling assays, confocal/TIRF microscopy, WASP activation assays, metabolic (glycolysis) assays |
Cell death & disease |
High |
39616183
|