{"gene":"DOCK2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"DOCK2 is essential for lymphocyte chemotaxis: DOCK2-deficient mice show abolished chemokine-induced Rac activation and actin polymerization in T and B lymphocytes, establishing DOCK2 as the central Rac GEF mediating cytoskeletal reorganization downstream of chemokine receptors in lymphocytes.","method":"DOCK2 knockout mouse model; Rac activation assay; actin polymerization assay; chemotaxis assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype (abolished Rac activation and actin polymerization), replicated across multiple cell types and assays, landmark paper widely confirmed by subsequent work","pmids":["11518968"],"is_preprint":false},{"year":1999,"finding":"DOCK2 (originally KIAA0209) binds to and activates Rac1, similar to DOCK180, but unlike DOCK180 it does not bind CrkII adaptor, indicating hematopoietic-specific Rac regulation independent of focal adhesion signaling.","method":"Pulldown/binding assay; Rac1 activation assay; expression analysis in tissue panels","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, pulldown and activation assay, confirmed by subsequent studies; initial characterization paper","pmids":["10559471"],"is_preprint":false},{"year":2003,"finding":"DOCK2 associates with ELMO1 through its SH3 domain, and this DOCK2-ELMO1 interaction is required for DOCK2-mediated Rac activation and actin polymerization; a DOCK2 mutant lacking the ELMO1-binding region fails to activate Rac or polymerize actin.","method":"Co-immunoprecipitation; DOCK2 domain deletion mutants; Rac activation assay; actin polymerization assay in T-hybridoma cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays plus loss-of-function mutant with defined mechanistic readout, replicated and extended by structural studies","pmids":["12829596"],"is_preprint":false},{"year":2003,"finding":"DOCK2 is essential for TCR-mediated Rac activation and immunological synapse formation; DOCK2-deficient T cells show severely impaired antigen-induced translocation of TCR and lipid rafts (but not PKC-θ or LFA-1) to the APC interface, leading to reduced T cell proliferation.","method":"DOCK2 knockout T cells; immunofluorescence of immunological synapse components; antigen-specific proliferation assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with specific mechanistic dissection of synapse component translocation using multiple markers","pmids":["12871644"],"is_preprint":false},{"year":2004,"finding":"HIV-1 Nef binds the DOCK2-ELMO1 complex (identified by mass spectrometry from T cells) and Rac, and activates Rac by binding this complex; this interaction underlies Nef-mediated inhibition of T cell chemotaxis and promotion of T cell activation.","method":"Proteomic purification of Nef-associated complex; mass spectrometry identification; Rac activation assay; chemotaxis assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — near-homogeneity purification + MS identification of DOCK2-ELMO1-Rac complex, functional validation by Rac activation and chemotaxis assays in a single rigorous study","pmids":["14737186"],"is_preprint":false},{"year":2004,"finding":"DOCK2 mediates efficient lymphocyte migration in a largely PI3K-independent manner; a residual PI3K-dependent migration pathway exists (PI3Kγ in T cells, other PI3K isoforms in B cells). DOCK2 is required for integrin activation in B cells but not T cells during chemokine-triggered responses.","method":"DOCK2-/- and PI3Kγ-/- mouse models; in vitro adhesion assays; intravital microscopy of lymphoid organ vasculature","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using double-KO mice combined with intravital microscopy and multiple adhesion assays","pmids":["15357953"],"is_preprint":false},{"year":2006,"finding":"DOCK2 regulates motility and polarity during neutrophil chemotaxis by activating both Rac1 and Rac2; DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a PI3K-dependent manner, enabling polarized accumulation of F-actin and PIP3.","method":"DOCK2-/- neutrophils; Rac1/Rac2 activation assays; live-cell imaging of PIP3 and F-actin localization; translocation assay with PI3K inhibition","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO plus live imaging identifying PIP3-dependent membrane translocation as mechanism; multiple orthogonal readouts","pmids":["16943182"],"is_preprint":false},{"year":2007,"finding":"DOCK2 is required for T cell receptor-mediated phosphorylation of the microtubule-destabilizing protein stathmin and for lysosomal trafficking and degradation of IL-4Rα, thereby controlling Th2 lineage commitment by preventing sustained IL-4R signaling.","method":"DOCK2-/- mice; phosphorylation assay for stathmin; IL-4Rα surface expression and lysosomal trafficking assays; Th2 differentiation analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple mechanistic readouts (stathmin phosphorylation, receptor trafficking, cytokine signaling) in a single focused study","pmids":["17767160"],"is_preprint":false},{"year":2007,"finding":"DOCK2 (and to a lesser extent PI3Kγ) is required for interstitial T and B cell motility within peripheral lymph nodes and for S1P-triggered lymphocyte migration and egress from lymph nodes, as established by multiphoton intravital microscopy.","method":"Multiphoton intravital microscopy of DOCK2-/- and PI3Kγ-/- mouse PLNs; S1P-induced migration assay; F-actin and PKB phosphorylation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct intravital imaging of KO mice plus in vitro mechanistic assays, multiple signaling readouts","pmids":["17325199"],"is_preprint":false},{"year":2008,"finding":"DOCK2 is required for Rac activation and chemotaxis of plasmacytoid dendritic cells (pDCs) but not myeloid dendritic cells, indicating that pDCs and mDCs use distinct molecules to activate Rac during chemotaxis.","method":"DOCK2-/- mouse; Rac activation assay in pDCs and mDCs; chemotaxis assay; adoptive transfer experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with Rac activation assay, chemotaxis assay, and in vivo adoptive transfer validation","pmids":["18198348"],"is_preprint":false},{"year":2010,"finding":"DOCK2 is essential for TLR7- and TLR9-mediated IFN-α induction in plasmacytoid dendritic cells: nucleic acid ligands induce Rac activation through a TLR-independent, DOCK2-dependent mechanism; this Rac activation drives IKK-α phosphorylation and IRF-7 nuclear translocation required for IFN-α production.","method":"DOCK2-/- pDCs; Rac activation assay; IKK-α phosphorylation assay; IRF-7 nuclear translocation assay; dominant-negative Rac expression in wild-type pDCs","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO plus dominant-negative Rac rescue, multiple orthogonal mechanistic readouts (Rac, IKKα, IRF7)","pmids":["20231379"],"is_preprint":false},{"year":2011,"finding":"The inflammasome adaptor ASC controls mRNA stability and expression of DOCK2 (independently of NLRP3 or caspase-1); ectopic DOCK2 expression in ASC-deficient cells restores Rac-mediated actin polymerization, antigen uptake, and chemotaxis, placing DOCK2 downstream of ASC in adaptive immune cell function.","method":"ASC-/- mice; genome-wide mRNA stability analysis; DOCK2 retroviral rescue experiments; Rac activation, actin polymerization, antigen uptake, and chemotaxis assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO plus rescue experiment with multiple orthogonal functional readouts; identifies ASC as upstream regulator of DOCK2 expression","pmids":["21892172"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the DOCK2-ELMO1 N-terminal complex (2.1 Å) reveals that the C-terminal Pro-rich tail of ELMO1 winds around the SH3 domain of DOCK2 forming an intermolecular five-helix bundle; ELMO1 binding relieves DOCK2 autoinhibition (mediated by interaction between its ELMO-interacting region and DHR-2 domain), and DOCK2 binding simultaneously relieves ELMO1 autoinhibition to permit RhoG binding and membrane localization.","method":"X-ray crystallography (2.1 Å); mutagenesis; domain binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation; identifies autoinhibition mechanism and mutual relief upon complex formation","pmids":["22331897"],"is_preprint":false},{"year":2012,"finding":"CPYPP (4-[3'-(2''-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione) binds reversibly to the DOCK2 DHR-2 catalytic domain and inhibits its GEF activity in vitro; in lymphocytes, CPYPP blocks both chemokine receptor- and antigen receptor-mediated Rac activation, chemotaxis, and T cell activation.","method":"In vitro GEF activity assay; compound binding assay to DHR-2; Rac activation assay in lymphocytes; chemotaxis and T cell activation assays","journal":"Chemistry & biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with defined binding to catalytic domain plus cellular functional assays; single lab but multiple orthogonal methods","pmids":["22520755"],"is_preprint":false},{"year":2012,"finding":"DOCK2 dimerization via lobe A of the DHR-2 domain is required for effective Rac activation during cell migration; the lobe A deletion mutant retains in vitro GEF activity but fails to activate Rac effectively at the plasma membrane, as shown by FRET analysis, indicating dimerization enables efficient Rac engagement in vivo.","method":"DOCK2 lobe A deletion and point mutants; FRET analysis; Rac activation assay; motility and polarity assays in thymoma cells and primary T cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro GEF assay + FRET live-cell imaging + loss-of-function mutants in primary cells; single lab with multiple orthogonal methods","pmids":["23050005"],"is_preprint":false},{"year":2002,"finding":"DOCK2 associates with CrkL (a hematopoietic-specific adaptor) through two separate regions of DOCK2 binding the CrkL SH3 domain; CrkL-induced Rac1 activation is inhibited by a dominant-negative DOCK2 mutant; DOCK2 also associates with Vav GEF in Jurkat cells, suggesting a CrkL-DOCK2-Vav complex regulates Rac1 in leukocytes.","method":"Co-immunoprecipitation in vivo and in vitro; Rac1 activation assay; immunocytochemistry colocalization; stable DOCK2 mutant expression in Jurkat cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and Rac activation assay, single lab, multiple binding partners identified","pmids":["12393632"],"is_preprint":false},{"year":2002,"finding":"DOCK2 associates with the CD3ζ subunit of the TCR complex in Jurkat cells and activates Rac2; DOCK2-mediated Rac2 activation enhances IL-2 promoter transcriptional activity, and dominant-negative Rac2 suppresses this effect.","method":"Co-immunoprecipitation; Rac2 activation assay; IL-2 promoter-luciferase reporter assay; dominant-negative Rac2 expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus activation assay plus reporter assay; single lab, two orthogonal methods","pmids":["12176041"],"is_preprint":false},{"year":2013,"finding":"DOCK2 is required for NK cell-mediated cytotoxicity: DOCK2-deficient NK cells fail to form lytic synapses due to almost complete loss of NKG2D-mediated Rac activation, despite normal conjugate formation with target cells; selective abrogation of DOCK2 GEF activity recapitulates this defect.","method":"DOCK2-/- NK cells; in vitro leukemia cell killing assay; in vivo MHC class I-deficient bone marrow rejection model; lytic synapse formation assay; Rac activation assay; GEF-dead DOCK2 mutant","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO plus GEF-dead mutant; in vitro and in vivo killing assays plus mechanistic Rac activation and synapse formation assays","pmids":["23719299"],"is_preprint":false},{"year":2014,"finding":"Elmo1, but not Elmo2, constitutively interacts with Dock2 in primary T lymphocytes; Elmo1 deficiency reduces Dock2 protein levels ~4-fold by promoting Dock2 polyubiquitination and proteasomal degradation, while Elmo1 overexpression inhibits Dock2 ubiquitination; Elmo1 interaction is required for Dock2-dependent Rac activation and chemotaxis.","method":"Elmo1-/- mice; Co-IP in primary T cells; ubiquitination assay; proteasome inhibitor rescue; transfection of Elmo1 mutants; Rac activation and chemotaxis assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, proteasome rescue, mutant rescue) in primary T cells from KO mice","pmids":["24821968"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structures of DOCK2-ELMO1 alone and as a ternary complex with RAC1 show that the binary complex adopts a closed auto-inhibited conformation; conformational change of ELMO1 to an open state exposes RAC1 binding sites on DOCK2-DHR2 and binding sites for RHOG and BAI GPCRs on ELMO1; upstream effectors including DOCK2 and ELMO1 phosphorylation destabilize the auto-inhibited state.","method":"Cryo-EM structure determination; crystal structure of RHOG-ELMO2-RBD complex; functional mutagenesis analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM and crystal structures with functional mutagenesis; independent structural validation of autoinhibition mechanism previously identified biochemically","pmids":["32651375"],"is_preprint":false},{"year":2018,"finding":"Wnt5a induces ROR1 to recruit DOCK2 via the cytoplasmic proline-rich domain (PRD) of ROR1, specifically requiring Pro808; this ROR1-DOCK2 interaction activates Rac1/2 in CLL cells and is required for Wnt5a-driven CLL cell proliferation.","method":"Co-immunoprecipitation; ROR1 truncation and point mutants; DOCK2 siRNA knockdown; Rac1/2 activation assay; proliferation assay; cirmtuzumab blocking","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping and single-residue mutagenesis (P808A) plus functional Rac activation and proliferation assays; single lab with multiple orthogonal methods","pmids":["29678828"],"is_preprint":false},{"year":2018,"finding":"Cholesterol sulfate (CS) binds to the catalytic DHR-2 domain of DOCK2 and suppresses its GEF activity, inhibiting DOCK2-mediated Rac activation and leukocyte migration; CS is the most abundantly produced in the Harderian gland via SULT2B1b/a sulfotransferases, and Sult2b1 knockout mice show augmented ocular surface inflammation.","method":"In vitro GEF activity assay; CS binding assay to DOCK2 DHR-2; mass spectrometric quantification of CS; Sult2b1 knockout mice; ocular inflammation model; leukocyte migration assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic inhibition assay with defined binding to catalytic domain, in vivo KO validation, and identification of endogenous inhibitor source; multiple orthogonal methods","pmids":["30065028"],"is_preprint":false},{"year":2017,"finding":"PIP3-dependent recruitment and activation of DOCK2 at the plasma membrane is required for sustained growth of BCR microclusters through F-actin cytoskeleton remodeling; DOCK2 deficiency disrupts B cell immunological synapse structure.","method":"DOCK2-/- B cells; PI3K inhibition; live-cell imaging of BCR microclusters; F-actin assay; B cell immunological synapse imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO plus PI3K inhibition with live imaging and F-actin mechanistic readouts in primary B cells","pmids":["29186690"],"is_preprint":false},{"year":2018,"finding":"DOCK2 is required for BCR-mediated Rac activation in B cells; DOCK2-deficient B cells show defects in B cell spreading, sustained BCR microcluster growth, and plasma cell differentiation both in vitro and in vivo, implicating the DOCK2-Rac axis in IgG antibody responses.","method":"DOCK2-/- B cells; conditional DOCK2 knockout (B cell lineage); Rac activation assay; B cell spreading assay; BCR microcluster imaging; plasma cell differentiation assay in vitro and in vivo; adoptive transfer","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus global KO with multiple in vitro and in vivo functional assays and mechanistic readouts","pmids":["29503648"],"is_preprint":false},{"year":2016,"finding":"DOCK2 co-immunoprecipitates with wild-type FLT3 and FLT3/ITD in leukemia cells; DOCK2 knockdown selectively reduces proliferation and colony formation in leukemia cells with elevated FLT3 activity and sensitizes FLT3/ITD cells to cytarabine.","method":"Mass spectrometry screen for FLT3-interacting proteins; co-immunoprecipitation; shRNA knockdown; proliferation, colony formation, and cell survival assays; mouse xenograft model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS identification plus Co-IP confirmed interaction; functional KD assays in cell lines and xenograft; single lab","pmids":["27748370"],"is_preprint":false},{"year":2022,"finding":"After fungal stimulation, SYK phosphorylates DOCK2 at tyrosine residues Y985 and Y1405, promoting recruitment and activation of Rac GTPases, which increases ROS production and downstream antifungal signaling in macrophages.","method":"Phosphorylation assay; site-directed mutagenesis of DOCK2 tyrosine residues; Rac activation assay; ROS production assay; DOCK2-/- macrophages; in vivo fungal infection model","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — identification of specific phosphorylation sites by mutagenesis with mechanistic Rac activation and ROS assays; single lab but multiple orthogonal methods","pmids":["35079145"],"is_preprint":false},{"year":2016,"finding":"DOCK2 (together with SOS1 and ARHGEF1) mediates JAK-dependent CXCL12-induced LFA-1 activation and Rac1 activation in human primary T lymphocytes; DOCK2 is tyrosine-phosphorylated upon chemokine signaling in a JAK- and pertussis toxin-sensitive manner.","method":"DOCK2 siRNA knockdown; LFA-1 adhesion assay under flow; Rac1 activation assay; tyrosine phosphorylation assay; JAK inhibitor treatment; pertussis toxin pretreatment","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional adhesion and Rac activation assays in primary human T cells; identifies JAK-DOCK2 phosphorylation axis; single lab","pmids":["27986909"],"is_preprint":false},{"year":2023,"finding":"DOCK2 regulates MRGPRB2-mediated mast cell degranulation through Rac activation and PAK1 phosphorylation; DOCK2-deficient mast cells show impaired MRGPRB2-mediated Rac activation and PAK1 phosphorylation while calcium influx and other signaling molecules are unaffected.","method":"DOCK2-/- mice; mast cell degranulation assay (compound 48/80, ciprofloxacin); Rac activation assay; PAK1 phosphorylation assay; calcium flux assay; small-molecule DOCK2 inhibitors; systemic and cutaneous anaphylaxis models","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO plus pharmacological inhibition with mechanistic dissection separating Rac-PAK1 from calcium pathway; multiple orthogonal methods and in vivo confirmation","pmids":["36804596"],"is_preprint":false},{"year":2023,"finding":"Cholesterol sulfate synthesized by SULT2B1 in tumor cells suppresses DOCK2 enzymatic GEF activity in T cells, promoting CD8+ T cell exhaustion in the HCC tumor microenvironment; tolazamide reverses DOCK2 inactivation-mediated T cell exhaustion.","method":"Quasi-targeted metabolomics; mass spectrometry; mass cytometry (CyTOF); DOCK2 GEF activity assay; flow cytometry; mouse HCC models; virtual screening and molecular docking","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GEF activity assay plus multiple orthogonal cell biology methods; single lab; extends the cholesterol sulfate-DOCK2 inhibition finding to the tumor microenvironment","pmids":["36626623"],"is_preprint":false},{"year":2023,"finding":"DOCK2 generates characteristic spatiotemporal patterns of Rac activity (visualized by live TIRF-FRET imaging in primary neutrophils) that are specifically required for neutrophil polarization, random migration, chemotaxis speed and turning, and rapid phagocytosis; Dock2 deficiency abolishes these spatially distinct Rac pools at leading edges.","method":"Live TIRF-FRET imaging with Rac-FRET reporter mice; DOCK2-/-, Tiam1-/-, Prex1-/-Vav1-/- neutrophils; polarization, migration velocity, chemotaxis, and phagocytosis assays; in vivo peritonitis model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct live-cell FRET imaging of Rac activity pools combined with multiple KO comparisons and in vivo validation; single lab with multiple orthogonal methods","pmids":["37383235"],"is_preprint":false},{"year":2025,"finding":"The transcription factor SUB1, induced by the TCR-IRF4 axis, directly trans-activates DOCK2 transcription by forming liquid-liquid phase separation condensates that open chromatin at the Dock2 locus and partners with JUNB to amplify Dock2 expression; conditional Sub1 deletion reduces DOCK2 expression, impairs Rac-dependent actin polymerization and T cell motility, and prevents experimental autoimmune encephalomyelitis.","method":"Conditional T cell-specific Sub1 KO mice; chromatin accessibility assay; ChIP; phase separation assay; transcriptional reporter assay; DOCK2 expression assay; Rac activation; actin polymerization; EAE model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (ChIP, phase separation, reporter assay, in vivo KO) in a single rigorous study identifying the TCR-SUB1-DOCK2 transcriptional axis","pmids":["41371223"],"is_preprint":false},{"year":2025,"finding":"CD11c (integrin αX) physically associates with DOCK2 intracellularly in neutrophils (confirmed by co-immunoprecipitation and proteomics); CD11c-deficient neutrophils show reduced DOCK2 phosphorylation and impaired Rac activation, leading to selective defects in ROS/NADPH oxidase activity without affecting phagocytosis.","method":"Phosphoproteomic profiling of CD11c-/- neutrophils; co-immunoprecipitation + proteomics; ROS production assay; phagocytosis assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus proteomics plus functional assays; single lab; identifies CD11c as upstream regulator of DOCK2 phosphorylation and Rac activity in neutrophils","pmids":["41268550"],"is_preprint":false},{"year":2016,"finding":"Inhibitory peptides discovered by T7 phage display bind the DOCK2 catalytic domain and block DOCK2-Rac1 protein-protein interaction at nanomolar concentrations; cell-penetrating peptide conjugation enables intracellular delivery and inhibition of B cell migration (IC50 ~120 nM).","method":"Random peptide T7 phage display; in vitro DOCK2 GEF inhibition assay; cell migration assay; cellular internalization assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro GEF inhibition assay with defined binding plus cell migration assay; single lab, focused on drug development","pmids":["28039053"],"is_preprint":false},{"year":2022,"finding":"DOCK2 inhibition with CPYPP increased severity of SARS-CoV-2 pneumonia in a Syrian hamster model, characterized by impaired macrophage recruitment and dysregulated type I interferon responses, demonstrating that DOCK2 function is required for macrophage-mediated antiviral immunity.","method":"DOCK2 inhibitor (CPYPP) treatment in Syrian hamster SARS-CoV-2 model; viral load measurement; macrophage recruitment assay; type I IFN response assay","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition in in vivo infection model with defined cellular and molecular readouts; single study but in a relevant in vivo system","pmids":["35940203"],"is_preprint":false},{"year":2022,"finding":"DOCK2 promotes TGF-β-induced fibroblast-to-myofibroblast transition (FMT) in lung fibroblasts; TGF-β upregulates DOCK2 expression via both Smad3 and ERK pathways and also stabilizes DOCK2 protein; DOCK2 knockdown attenuates α-SMA, collagen-1, and fibronectin induction; DOCK2-/- mice are protected from bleomycin-induced pulmonary fibrosis.","method":"DOCK2 siRNA knockdown in primary human lung fibroblasts; Smad3/ERK inhibitors; DOCK2-/- mouse bleomycin model; Western blot for FMT markers","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with pathway inhibitors plus in vivo KO model; single lab; identifies Smad3/ERK-DOCK2-FMT axis","pmids":["35584329"],"is_preprint":false},{"year":2023,"finding":"DOCK2 interacts with transcription factor FoxM1 and enhances FoxM1 binding to mesenchymal marker gene promoters, promoting mesenchymal marker gene transcription and EMT in airway epithelial cells downstream of TGF-β1 stimulation.","method":"DOCK2-FoxM1 co-immunoprecipitation; ChIP assay for FoxM1 promoter binding; DOCK2 KD and overexpression; TGF-β1-induced EMT assay; DOCK2-/- HDM-induced asthma mouse model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP for mechanistic pathway placement; in vivo KO validation; single lab","pmids":["36883952"],"is_preprint":false},{"year":2020,"finding":"DOCK2-mediated Rac activation is required for TLR4-induced inflammatory responses in macrophages; LPS induces Rac activation through a TLR4-independent, DOCK2-dependent mechanism; DOCK2-Rac signaling controls IKKβ activation and NF-κB nuclear translocation for inflammatory cytokine release.","method":"Ad-shDOCK2 macrophages; Rac activation assay; IKKβ phosphorylation assay; NF-κB nuclear translocation assay; CPYPP pharmacological inhibition; LPS-induced ALI mouse model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD plus Rac inhibitor with mechanistic signaling readouts and in vivo pharmacological confirmation; single lab","pmids":["33382969"],"is_preprint":false},{"year":2009,"finding":"DOCK2 is expressed specifically in microglia in the brain and regulates microglial innate immunity (cytokine secretion, phagocytosis, paracrine neurotoxicity) independently of COX2 induction; DOCK2 links to prostaglandin E2 receptor EP2 signaling in the brain.","method":"Immunohistochemistry of human AD brain; DOCK2-/- microglial functional assays (cytokine, phagocytosis, neurotoxicity); EP2-DOCK2 pathway analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KO functional assays in microglia with multiple readouts; single lab; localization established by IHC with functional follow-up","pmids":["19729484"],"is_preprint":false},{"year":2020,"finding":"Wnt5a induces ERK1/2 phosphorylation and CLL cell proliferation via ROR1/DOCK2-dependent pathway; DOCK2 siRNA knockdown blocks Wnt5a-induced ERK1/2 phosphorylation, and ROR1P808A (unable to recruit DOCK2) fails to mediate these effects; ibrutinib cannot inhibit this Wnt5a-ROR1-DOCK2-ERK1/2 axis.","method":"DOCK2 siRNA; ROR1 mutants (ΔPRD, P808A); ERK1/2 phosphorylation assay; DOCK2 phosphorylation assay; CLL cell proliferation assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD plus domain mutants with phosphorylation and proliferation readouts; single lab; extends prior ROR1-DOCK2 finding","pmids":["33097837"],"is_preprint":false}],"current_model":"DOCK2 is a hematopoietic cell-specific, atypical Rac-GEF that lacks a Dbl-homology domain but mediates GTP-GDP exchange for Rac1 and Rac2 via its DHR-2 (CZH2) catalytic domain; it forms an obligate complex with ELMO1 through its SH3 domain (structurally characterized by both X-ray crystallography and cryo-EM), with ELMO1 binding mutually relieving autoinhibition in both partners and preventing proteasomal degradation of DOCK2; PIP3 recruits DOCK2 to the plasma membrane in a PI3K-dependent manner; once activated, DOCK2-Rac signaling drives actin polymerization, lamellipodia formation, cell polarization, immunological synapse formation, BCR microcluster growth, lytic granule polarization, and type I IFN induction via IKKα-IRF7 in plasmacytoid dendritic cells; upstream activators include chemokine receptors, TCR/CD3ζ, BCR, FLT3, ROR1 (via Wnt5a), NKG2D, MRGPRB2, SYK (phosphorylating Y985/Y1405 after fungal stimulation), CD11c, and the transcription factor SUB1 (which opens the Dock2 chromatin locus downstream of TCR-IRF4); endogenous inhibition is provided by cholesterol sulfate binding to the DHR-2 domain; small-molecule inhibitor CPYPP and peptide inhibitors targeting the DOCK2-Rac1 interface block its catalytic activity."},"narrative":{"mechanistic_narrative":"DOCK2 is a hematopoietic cell-enriched, atypical guanine nucleotide exchange factor that serves as the central activator of Rac GTPases (Rac1 and Rac2) driving actin-dependent cytoskeletal reorganization throughout the immune system [PMID:11518968, PMID:10559471, PMID:16943182]. In lymphocytes, DOCK2 is required for chemokine-induced Rac activation and actin polymerization, and its loss abolishes chemotaxis [PMID:11518968]. DOCK2 functions as an obligate partner of ELMO1: it binds ELMO1 through its SH3 domain, and this association is required for Rac activation and actin polymerization, mutually relieving autoinhibition in both proteins and protecting DOCK2 from polyubiquitination and proteasomal degradation [PMID:12829596, PMID:22331897, PMID:24821968, PMID:32651375]. Catalysis is executed by the DHR-2 domain, whose activity additionally requires lobe A-mediated dimerization for efficient Rac engagement at the membrane [PMID:22520755, PMID:23050005]. DOCK2 is recruited to the plasma membrane and leading edge by PIP3 in a PI3K-dependent manner, generating spatially defined pools of active Rac that pattern cell polarization, migration, and phagocytosis [PMID:16943182, PMID:29186690, PMID:37383235]. Through this axis DOCK2 controls immunological synapse formation and TCR/lipid-raft translocation in T cells [PMID:12871644], BCR microcluster growth and plasma cell differentiation in B cells [PMID:29186690, PMID:29503648], lytic synapse formation in NK cells [PMID:23719299], mast cell degranulation via Rac-PAK1 [PMID:36804596], and TLR7/9-driven IFN-α induction in plasmacytoid dendritic cells through Rac-dependent IKKα phosphorylation and IRF-7 nuclear translocation [PMID:20231379]. DOCK2 is engaged by diverse upstream receptors and kinases, including the CD3ζ chain of the TCR [PMID:12176041], SYK (which phosphorylates Y985/Y1405 after fungal stimulation) [PMID:35079145], FLT3 [PMID:27748370], ROR1 downstream of Wnt5a [PMID:29678828], and CD11c [PMID:41268550], and its expression is transcriptionally controlled by the TCR-IRF4-SUB1 axis [PMID:41371223]. Endogenous inhibition is provided by cholesterol sulfate binding to the DHR-2 domain, a mechanism exploited in the tumor microenvironment to drive CD8+ T cell exhaustion [PMID:30065028, PMID:36626623], and DOCK2 catalysis is pharmacologically blocked by the small molecule CPYPP and by peptides targeting the DOCK2-Rac1 interface [PMID:22520755, PMID:28039053].","teleology":[{"year":1999,"claim":"Establishing that DOCK2 is a Rac1 activator distinct from focal-adhesion DOCK180 defined it as a candidate hematopoietic-specific Rac regulator.","evidence":"pulldown/binding and Rac1 activation assays with tissue expression analysis","pmids":["10559471"],"confidence":"Medium","gaps":["No catalytic mechanism or domain responsible for exchange defined","No in vivo phenotype"]},{"year":2001,"claim":"Genetic deletion showed DOCK2 is the central Rac GEF coupling chemokine receptors to cytoskeletal remodeling in lymphocytes, settling its physiological role.","evidence":"DOCK2 knockout mice with Rac activation, actin polymerization, and chemotaxis assays in T and B cells","pmids":["11518968"],"confidence":"High","gaps":["Receptor-to-DOCK2 coupling mechanism unresolved","Membrane recruitment mechanism not addressed"]},{"year":2002,"claim":"Identification of CD3ζ and CrkL/Vav associations placed DOCK2 within antigen- and adaptor-receptor signaling complexes that activate Rac2 and drive IL-2 transcription.","evidence":"co-immunoprecipitation, Rac activation, and IL-2 promoter reporter assays in Jurkat cells","pmids":["12176041","12393632"],"confidence":"Medium","gaps":["Single cell-line Co-IPs without reciprocal validation in primary cells","Direct vs. indirect binding not distinguished"]},{"year":2003,"claim":"Mapping the ELMO1 interaction to the DOCK2 SH3 domain and showing it is essential for Rac activation defined the obligate DOCK2-ELMO1 functional unit.","evidence":"Co-IP, domain-deletion mutants, and Rac/actin assays in T-hybridoma cells; KO T cells for synapse formation","pmids":["12829596","12871644"],"confidence":"High","gaps":["Structural basis of SH3-ELMO1 binding not yet defined","Whether ELMO1 affects DOCK2 stability not addressed"]},{"year":2004,"claim":"Defining a PI3K-largely-independent migration role and identifying HIV-1 Nef hijacking of the DOCK2-ELMO1-Rac complex clarified both physiological and pathogen-manipulated activation routes.","evidence":"double-KO mice with intravital microscopy; proteomic purification and MS of the Nef-associated complex with functional Rac/chemotaxis assays","pmids":["15357953","14737186"],"confidence":"High","gaps":["Relative contribution of PI3K vs PI3K-independent recruitment unresolved","Direct Nef-DOCK2 contact surface not mapped"]},{"year":2006,"claim":"Live imaging established that PIP3 recruits DOCK2 to the leading edge in a PI3K-dependent manner, providing the spatial mechanism for polarized Rac activation in neutrophils.","evidence":"DOCK2-/- neutrophils with Rac1/Rac2 assays, live-cell PIP3/F-actin imaging, and PI3K-inhibited translocation assays","pmids":["16943182"],"confidence":"High","gaps":["Lipid-binding determinant on DOCK2 not mapped","How dual Rac1/Rac2 selectivity is set is unclear"]},{"year":2007,"claim":"Showing DOCK2 controls stathmin phosphorylation, IL-4Rα trafficking, and lymphocyte interstitial motility/egress extended its role beyond chemotaxis into receptor trafficking and Th lineage decisions.","evidence":"DOCK2-/- mice with stathmin phosphorylation, receptor trafficking, Th2 differentiation assays, and multiphoton intravital microscopy","pmids":["17767160","17325199"],"confidence":"High","gaps":["Direct link from Rac to stathmin phosphorylation not established","Mechanism of IL-4Rα lysosomal targeting unresolved"]},{"year":2008,"claim":"Cell-type comparisons revealed DOCK2 is required for Rac activation in plasmacytoid but not myeloid dendritic cells, demonstrating lineage-specific Rac-GEF wiring.","evidence":"DOCK2-/- pDC vs mDC Rac activation, chemotaxis, and adoptive transfer assays","pmids":["18198348"],"confidence":"High","gaps":["Identity of the mDC Rac GEF not addressed","Basis of pDC-specific dependence unknown"]},{"year":2010,"claim":"Linking DOCK2-Rac to IKKα phosphorylation and IRF-7 nuclear translocation defined the signaling route from TLR7/9 nucleic-acid sensing to type I IFN production in pDCs.","evidence":"DOCK2-/- pDCs with Rac, IKKα phosphorylation, IRF-7 translocation assays and dominant-negative Rac rescue","pmids":["20231379"],"confidence":"High","gaps":["How nucleic acid sensing activates DOCK2 TLR-independently is unresolved","Direct Rac-to-IKKα link not biochemically defined"]},{"year":2011,"claim":"Identifying ASC as a controller of DOCK2 mRNA stability placed DOCK2 expression under inflammasome-adaptor regulation independent of caspase-1.","evidence":"ASC-/- mice, genome-wide mRNA stability analysis, and DOCK2 retroviral rescue of Rac/actin/chemotaxis defects","pmids":["21892172"],"confidence":"High","gaps":["Molecular mechanism by which ASC stabilizes DOCK2 mRNA unknown"]},{"year":2012,"claim":"Crystallography, dimerization analysis, and a catalytic-domain inhibitor together defined DOCK2's autoinhibition, the structural basis of mutual relief with ELMO1, and the requirement for DHR-2 dimerization in vivo.","evidence":"2.1 Å crystal structure of DOCK2-ELMO1 with mutagenesis; lobe A deletion mutants with FRET; CPYPP GEF inhibition and cellular assays","pmids":["22331897","23050005","22520755"],"confidence":"High","gaps":["Full-length conformational dynamics not captured at this stage","How upstream signals trigger the autoinhibition switch not defined"]},{"year":2013,"claim":"Demonstrating that DOCK2 GEF activity is required for NKG2D-driven lytic synapse formation extended its Rac-activating role to NK-cell cytotoxicity.","evidence":"DOCK2-/- and GEF-dead NK cells with killing, lytic synapse, and Rac activation assays plus in vivo BM rejection model","pmids":["23719299"],"confidence":"High","gaps":["Coupling of NKG2D to DOCK2 not biochemically mapped"]},{"year":2014,"claim":"Showing ELMO1 prevents DOCK2 polyubiquitination established that complex formation is also a protein-stability mechanism, not merely an activation switch.","evidence":"Elmo1-/- mice, Co-IP, ubiquitination assays, proteasome-inhibitor rescue, and mutant rescue in primary T cells","pmids":["24821968"],"confidence":"High","gaps":["E3 ligase targeting DOCK2 not identified","Why Elmo2 cannot substitute is unexplained"]},{"year":2016,"claim":"Receptor-coupling studies and inhibitory-peptide work connected DOCK2 to FLT3 and JAK/chemokine signaling and validated the DOCK2-Rac1 interface as a druggable surface.","evidence":"MS/Co-IP with FLT3, shRNA functional assays; siRNA with LFA-1/Rac and phosphorylation assays; phage-display peptide GEF inhibition and migration assays","pmids":["27748370","27986909","28039053"],"confidence":"Medium","gaps":["Direct vs scaffold-mediated FLT3-DOCK2 contact not resolved","JAK phosphosites on DOCK2 not mapped"]},{"year":2018,"claim":"Identifying cholesterol sulfate as an endogenous DHR-2 inhibitor and ROR1 as a Wnt5a-driven recruiter defined both a physiological brake and an oncogenic activation route for DOCK2.","evidence":"in vitro GEF/binding assays, Sult2b1-/- ocular inflammation model; ROR1 P808A mutagenesis with Co-IP and Rac/proliferation assays in CLL","pmids":["30065028","29678828"],"confidence":"High","gaps":["Cholesterol sulfate binding site on DHR-2 not structurally defined","Whether ROR1 recruitment requires ELMO1 not addressed"]},{"year":2018,"claim":"B-cell genetics established that PIP3-recruited DOCK2 sustains BCR microcluster growth and is required for plasma cell differentiation and antibody responses.","evidence":"DOCK2-/- and conditional KO B cells with PI3K inhibition, microcluster/F-actin imaging, and in vitro/in vivo plasma cell assays","pmids":["29186690","29503648"],"confidence":"High","gaps":["Direct effectors linking Rac to BCR microcluster stability not defined"]},{"year":2020,"claim":"Cryo-EM of binary and RAC1-ternary complexes provided independent structural confirmation of the closed autoinhibited state and how the open ELMO1 conformation exposes RAC1, RHOG, and BAI-GPCR binding sites.","evidence":"cryo-EM structures, RHOG-ELMO2-RBD crystal structure, and functional mutagenesis","pmids":["32651375"],"confidence":"High","gaps":["Physiological trigger ordering of phosphorylation vs membrane recruitment not resolved"]},{"year":2020,"claim":"Extending DOCK2-Rac to innate macrophage signaling showed it controls TLR4-induced IKKβ/NF-κB activation and microglial innate immunity, broadening its inflammatory roles.","evidence":"shRNA and CPYPP in macrophages with Rac/IKKβ/NF-κB assays and ALI model; DOCK2-/- microglia functional assays","pmids":["33382969","19729484"],"confidence":"Medium","gaps":["Mechanism of TLR4-independent LPS-induced Rac activation unresolved","Direct Rac-to-IKKβ link not biochemically defined"]},{"year":2022,"claim":"Identifying SYK phosphosites (Y985/Y1405) and a CPYPP-revealed antiviral macrophage role defined post-translational activation and protective innate functions of DOCK2.","evidence":"site-directed mutagenesis with Rac/ROS assays after fungal stimulation; CPYPP in a hamster SARS-CoV-2 model with macrophage and IFN readouts; TGF-β fibrosis model","pmids":["35079145","35940203","35584329"],"confidence":"High","gaps":["How phosphorylation couples to DHR-2 conformational change not defined","Fibrosis mechanism (Rac-dependence) not fully dissected"]},{"year":2023,"claim":"Studies in mast cells, NK/T tumor immunity, neutrophil Rac patterning, CD11c coupling, and FoxM1-driven EMT mapped DOCK2's reach across degranulation, exhaustion, oxidative burst, and epithelial transcription programs.","evidence":"DOCK2-/- mast cells (Rac-PAK1); SULT2B1/cholesterol sulfate HCC models; TIRF-FRET Rac imaging in neutrophils; CD11c-/- phosphoproteomics; DOCK2-FoxM1 Co-IP/ChIP","pmids":["36804596","36626623","37383235","41268550","36883952"],"confidence":"High","gaps":["Whether nuclear DOCK2-FoxM1 function is Rac-dependent unclear","Mechanism of CD11c-driven DOCK2 phosphorylation not mapped"]},{"year":2025,"claim":"Identifying the TCR-IRF4-SUB1 axis as a phase-separation-driven transcriptional activator of DOCK2 closed a gap in how DOCK2 expression is induced during T cell activation.","evidence":"conditional Sub1 KO mice with chromatin accessibility, ChIP, phase-separation, reporter assays, Rac/actin readouts, and EAE model","pmids":["41371223"],"confidence":"High","gaps":["How SUB1 condensates select the Dock2 locus specifically not defined"]},{"year":null,"claim":"How upstream phosphorylation, PIP3 recruitment, and ELMO1-mediated conformational opening are integrated into a single ordered activation switch, and how this is differentially tuned across immune lineages, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified kinetic model integrating membrane, phospho, and conformational inputs","Lineage-specific differences in DOCK2 regulation not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,13,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[10,16,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,22,29]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,10,17,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,16,20,25,36]}],"complexes":["DOCK2-ELMO1 complex"],"partners":["ELMO1","RAC1","RAC2","CRKL","CD3Z","ROR1","FLT3","SYK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92608","full_name":"Dedicator of cytokinesis protein 2","aliases":[],"length_aa":1830,"mass_kda":211.9,"function":"Involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines. Activates RAC1 and RAC2, but not CDC42, by functioning as a guanine nucleotide exchange factor (GEF), which exchanges bound GDP for free GTP. May also participate in IL2 transcriptional activation via the activation of RAC2","subcellular_location":"Endomembrane system; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q92608/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOCK2","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DOCK2","total_profiled":1310},"omim":[{"mim_id":"616433","title":"IMMUNODEFICIENCY 40; IMD40","url":"https://www.omim.org/entry/616433"},{"mim_id":"606420","title":"ENGULFMENT AND CELL MOTILITY GENE 1; ELMO1","url":"https://www.omim.org/entry/606420"},{"mim_id":"603123","title":"DEDICATOR OF CYTOKINESIS 3; DOCK3","url":"https://www.omim.org/entry/603123"},{"mim_id":"603122","title":"DEDICATOR OF CYTOKINESIS 2; DOCK2","url":"https://www.omim.org/entry/603122"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":50.1},{"tissue":"lung","ntpm":14.7},{"tissue":"lymphoid tissue","ntpm":46.8}],"url":"https://www.proteinatlas.org/search/DOCK2"},"hgnc":{"alias_symbol":["KIAA0209"],"prev_symbol":[]},"alphafold":{"accession":"Q92608","domains":[{"cath_id":"2.30.30.40","chopping":"6-83","consensus_level":"high","plddt":82.2127,"start":6,"end":83},{"cath_id":"1.20.1270.350","chopping":"87-206","consensus_level":"high","plddt":85.8886,"start":87,"end":206},{"cath_id":"2.60.40.150","chopping":"210-418","consensus_level":"medium","plddt":84.3215,"start":210,"end":418},{"cath_id":"2.60.40.150","chopping":"423-575_591-612","consensus_level":"medium","plddt":89.4612,"start":423,"end":612},{"cath_id":"-","chopping":"1339-1493","consensus_level":"medium","plddt":86.1466,"start":1339,"end":1493}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92608","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92608-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92608-F1-predicted_aligned_error_v6.png","plddt_mean":79.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOCK2","jax_strain_url":"https://www.jax.org/strain/search?query=DOCK2"},"sequence":{"accession":"Q92608","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92608.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92608/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92608"}},"corpus_meta":[{"pmid":"35609983","id":"PMC_35609983","title":"CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/35609983","citation_count":1178,"is_preprint":false},{"pmid":"11518968","id":"PMC_11518968","title":"Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11518968","citation_count":361,"is_preprint":false},{"pmid":"15357953","id":"PMC_15357953","title":"Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing.","date":"2004","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15357953","citation_count":187,"is_preprint":false},{"pmid":"16943182","id":"PMC_16943182","title":"DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16943182","citation_count":170,"is_preprint":false},{"pmid":"26083206","id":"PMC_26083206","title":"Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.","date":"2015","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26083206","citation_count":160,"is_preprint":false},{"pmid":"17325199","id":"PMC_17325199","title":"A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress.","date":"2007","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17325199","citation_count":126,"is_preprint":false},{"pmid":"12871644","id":"PMC_12871644","title":"DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T cells.","date":"2003","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12871644","citation_count":107,"is_preprint":false},{"pmid":"14737186","id":"PMC_14737186","title":"HIV-1 Nef binds the DOCK2-ELMO1 complex to activate rac and inhibit lymphocyte chemotaxis.","date":"2004","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/14737186","citation_count":107,"is_preprint":false},{"pmid":"20231379","id":"PMC_20231379","title":"Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation.","date":"2010","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20231379","citation_count":98,"is_preprint":false},{"pmid":"21892172","id":"PMC_21892172","title":"The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21892172","citation_count":96,"is_preprint":false},{"pmid":"12829596","id":"PMC_12829596","title":"DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12829596","citation_count":95,"is_preprint":false},{"pmid":"35940203","id":"PMC_35940203","title":"DOCK2 is involved in the host genetics and biology of severe COVID-19.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35940203","citation_count":77,"is_preprint":false},{"pmid":"12191913","id":"PMC_12191913","title":"The CDM protein DOCK2 in lymphocyte migration.","date":"2002","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12191913","citation_count":77,"is_preprint":false},{"pmid":"10559471","id":"PMC_10559471","title":"Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10559471","citation_count":74,"is_preprint":false},{"pmid":"22431588","id":"PMC_22431588","title":"Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22431588","citation_count":72,"is_preprint":false},{"pmid":"22520755","id":"PMC_22520755","title":"Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2.","date":"2012","source":"Chemistry & biology","url":"https://pubmed.ncbi.nlm.nih.gov/22520755","citation_count":71,"is_preprint":false},{"pmid":"22331897","id":"PMC_22331897","title":"Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22331897","citation_count":68,"is_preprint":false},{"pmid":"17767160","id":"PMC_17767160","title":"T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha subunit controlled by the Rac activator Dock2.","date":"2007","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17767160","citation_count":68,"is_preprint":false},{"pmid":"12393632","id":"PMC_12393632","title":"DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12393632","citation_count":63,"is_preprint":false},{"pmid":"19451552","id":"PMC_19451552","title":"CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19451552","citation_count":59,"is_preprint":false},{"pmid":"18198348","id":"PMC_18198348","title":"Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18198348","citation_count":59,"is_preprint":false},{"pmid":"20412587","id":"PMC_20412587","title":"PI3Kp110-, Src-, FAK-dependent and DOCK2-independent migration and invasion of CXCL13-stimulated prostate cancer cells.","date":"2010","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20412587","citation_count":50,"is_preprint":false},{"pmid":"23719299","id":"PMC_23719299","title":"The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23719299","citation_count":50,"is_preprint":false},{"pmid":"32651375","id":"PMC_32651375","title":"Structure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32651375","citation_count":49,"is_preprint":false},{"pmid":"24821968","id":"PMC_24821968","title":"Essential role of Elmo1 in Dock2-dependent lymphocyte migration.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24821968","citation_count":45,"is_preprint":false},{"pmid":"23291967","id":"PMC_23291967","title":"Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2.","date":"2013","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23291967","citation_count":45,"is_preprint":false},{"pmid":"29678828","id":"PMC_29678828","title":"Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia.","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29678828","citation_count":44,"is_preprint":false},{"pmid":"29509960","id":"PMC_29509960","title":"Dock2 in the development of inflammation and cancer.","date":"2018","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29509960","citation_count":42,"is_preprint":false},{"pmid":"19729484","id":"PMC_19729484","title":"DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer's disease brain.","date":"2009","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19729484","citation_count":42,"is_preprint":false},{"pmid":"16230477","id":"PMC_16230477","title":"Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection.","date":"2005","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16230477","citation_count":40,"is_preprint":false},{"pmid":"36626623","id":"PMC_36626623","title":"SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment.","date":"2023","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/36626623","citation_count":39,"is_preprint":false},{"pmid":"37676595","id":"PMC_37676595","title":"Protein-Ligand Blind Docking Using CB-Dock2.","date":"2024","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/37676595","citation_count":38,"is_preprint":false},{"pmid":"30065028","id":"PMC_30065028","title":"Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/30065028","citation_count":36,"is_preprint":false},{"pmid":"33097837","id":"PMC_33097837","title":"Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism.","date":"2020","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/33097837","citation_count":35,"is_preprint":false},{"pmid":"30838481","id":"PMC_30838481","title":"Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction.","date":"2019","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30838481","citation_count":32,"is_preprint":false},{"pmid":"33382969","id":"PMC_33382969","title":"DOCK2 contributes to endotoxemia-induced acute lung injury in mice by activating proinflammatory macrophages.","date":"2020","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33382969","citation_count":32,"is_preprint":false},{"pmid":"17015707","id":"PMC_17015707","title":"DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin alpha4beta1.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17015707","citation_count":31,"is_preprint":false},{"pmid":"29186690","id":"PMC_29186690","title":"Growth of B Cell Receptor Microclusters Is Regulated by PIP2 and PIP3 Equilibrium and Dock2 Recruitment and Activation.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29186690","citation_count":30,"is_preprint":false},{"pmid":"23318649","id":"PMC_23318649","title":"Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease.","date":"2013","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23318649","citation_count":29,"is_preprint":false},{"pmid":"16585555","id":"PMC_16585555","title":"DOCK2 is required in T cell precursors for development of Valpha14 NK T cells.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16585555","citation_count":29,"is_preprint":false},{"pmid":"23050005","id":"PMC_23050005","title":"Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23050005","citation_count":28,"is_preprint":false},{"pmid":"25076492","id":"PMC_25076492","title":"Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25076492","citation_count":27,"is_preprint":false},{"pmid":"20350533","id":"PMC_20350533","title":"DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20350533","citation_count":25,"is_preprint":false},{"pmid":"12176041","id":"PMC_12176041","title":"DOCK2 mediates T cell receptor-induced activation of Rac2 and IL-2 transcription.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12176041","citation_count":25,"is_preprint":false},{"pmid":"35079145","id":"PMC_35079145","title":"DOCK2 regulates antifungal immunity by regulating RAC GTPase activity.","date":"2022","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35079145","citation_count":23,"is_preprint":false},{"pmid":"27748370","id":"PMC_27748370","title":"DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells.","date":"2016","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/27748370","citation_count":23,"is_preprint":false},{"pmid":"36250020","id":"PMC_36250020","title":"Insights from DOCK2 in cell function and pathophysiology.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36250020","citation_count":22,"is_preprint":false},{"pmid":"34710342","id":"PMC_34710342","title":"DOCK2 Promotes Pleural Fibrosis by Modulating Mesothelial to Mesenchymal Transition.","date":"2022","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34710342","citation_count":22,"is_preprint":false},{"pmid":"29503648","id":"PMC_29503648","title":"The Rac Activator DOCK2 Mediates Plasma Cell Differentiation and IgG Antibody Production.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29503648","citation_count":22,"is_preprint":false},{"pmid":"35584329","id":"PMC_35584329","title":"DOCK2 contributes to pulmonary fibrosis by promoting lung fibroblast to myofibroblast transition.","date":"2022","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35584329","citation_count":22,"is_preprint":false},{"pmid":"28039053","id":"PMC_28039053","title":"Novel DOCK2-selective inhibitory peptide that suppresses B-cell line migration.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28039053","citation_count":21,"is_preprint":false},{"pmid":"30826364","id":"PMC_30826364","title":"T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30826364","citation_count":20,"is_preprint":false},{"pmid":"28716822","id":"PMC_28716822","title":"DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure.","date":"2017","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/28716822","citation_count":19,"is_preprint":false},{"pmid":"34767813","id":"PMC_34767813","title":"Dedicator of Cytokinesis 2 (DOCK2) Deficiency Attenuates Lung Injury Associated with Chronic High-Fat and High-Fructose Diet-Induced Obesity.","date":"2021","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34767813","citation_count":19,"is_preprint":false},{"pmid":"25044556","id":"PMC_25044556","title":"DOCK2 is critical for CD8(+) TCR(-) graft facilitating cells to enhance engraftment of hematopoietic stem and progenitor cells.","date":"2014","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/25044556","citation_count":18,"is_preprint":false},{"pmid":"27986909","id":"PMC_27986909","title":"SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27986909","citation_count":17,"is_preprint":false},{"pmid":"36804596","id":"PMC_36804596","title":"DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis.","date":"2023","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36804596","citation_count":16,"is_preprint":false},{"pmid":"27890234","id":"PMC_27890234","title":"Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency: DOCK8 and DOCK2.","date":"2017","source":"Dermatologic clinics","url":"https://pubmed.ncbi.nlm.nih.gov/27890234","citation_count":14,"is_preprint":false},{"pmid":"30012848","id":"PMC_30012848","title":"B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30012848","citation_count":14,"is_preprint":false},{"pmid":"36883952","id":"PMC_36883952","title":"DOCK2 Promotes Asthma Development by Eliciting Airway Epithelial-Mesenchymal Transition.","date":"2023","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36883952","citation_count":13,"is_preprint":false},{"pmid":"33662140","id":"PMC_33662140","title":"The role of Dock2 on macrophage migration and functions during Citrobacter rodentium infection.","date":"2021","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33662140","citation_count":13,"is_preprint":false},{"pmid":"31740487","id":"PMC_31740487","title":"DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8+ T Cell Compartment by Negatively Regulating Tonic TCR Triggering.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31740487","citation_count":13,"is_preprint":false},{"pmid":"18157938","id":"PMC_18157938","title":"Dock2 participates in bone marrow lympho-hematopoiesis.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18157938","citation_count":13,"is_preprint":false},{"pmid":"28607113","id":"PMC_28607113","title":"Antigen Availability and DOCK2-Driven Motility Govern CD4+ T Cell Interactions with Dendritic Cells In Vivo.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28607113","citation_count":12,"is_preprint":false},{"pmid":"34391464","id":"PMC_34391464","title":"Dock2 affects the host susceptibility to Citrobacter rodentium infection through regulating gut microbiota.","date":"2021","source":"Gut pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/34391464","citation_count":12,"is_preprint":false},{"pmid":"36947335","id":"PMC_36947335","title":"Multiple Immune Defects in Two Patients with Novel DOCK2 Mutations Result in Recurrent Multiple Infection Including Live Attenuated Virus Vaccine.","date":"2023","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36947335","citation_count":11,"is_preprint":false},{"pmid":"19728314","id":"PMC_19728314","title":"Role of DOCK2 and DOCK180 in fetal thymus colonization.","date":"2009","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19728314","citation_count":10,"is_preprint":false},{"pmid":"32703426","id":"PMC_32703426","title":"DOCK2 couples with LEF-1 to regulate B cell metabolism and memory response.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32703426","citation_count":9,"is_preprint":false},{"pmid":"37383235","id":"PMC_37383235","title":"Dock2 generates characteristic spatiotemporal patterns of Rac activity to regulate neutrophil polarisation, migration and phagocytosis.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37383235","citation_count":9,"is_preprint":false},{"pmid":"34094683","id":"PMC_34094683","title":"Genetic variants of DOCK2, EPHB1 and VAV2 in the natural killer cell-related pathway are associated with non-small cell lung cancer survival.","date":"2021","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34094683","citation_count":9,"is_preprint":false},{"pmid":"37838011","id":"PMC_37838011","title":"DOCK2 Promotes Atherosclerosis by Mediating the Endothelial Cell Inflammatory Response.","date":"2023","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37838011","citation_count":8,"is_preprint":false},{"pmid":"39923106","id":"PMC_39923106","title":"Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation.","date":"2025","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/39923106","citation_count":8,"is_preprint":false},{"pmid":"38366567","id":"PMC_38366567","title":"DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection.","date":"2024","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38366567","citation_count":8,"is_preprint":false},{"pmid":"28284862","id":"PMC_28284862","title":"Investigation on cellular uptake and pharmacodynamics of DOCK2-inhibitory peptides conjugated with cell-penetrating peptides.","date":"2017","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28284862","citation_count":8,"is_preprint":false},{"pmid":"34872585","id":"PMC_34872585","title":"First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature.","date":"2021","source":"Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34872585","citation_count":8,"is_preprint":false},{"pmid":"38990461","id":"PMC_38990461","title":"Silencing DOCK2 Attenuates Cardiac Fibrosis Following Myocardial Infarction in Mice Via Targeting PI3K/Akt and Wnt/β-Catenin Pathways.","date":"2024","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/38990461","citation_count":7,"is_preprint":false},{"pmid":"35395356","id":"PMC_35395356","title":"Dedicator of Cytokinesis 2 (DOCK2) Silencing Protects Against Cerebral Ischemia/Reperfusion by Modulating Microglia Polarization via the Activation of the STAT6 Signaling Pathway.","date":"2022","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35395356","citation_count":7,"is_preprint":false},{"pmid":"35023658","id":"PMC_35023658","title":"Hematopoietic stem cell transplantation complicated with EBV associated hemophagocytic lymphohistiocytosis in a patient with DOCK2 deficiency.","date":"2021","source":"The Turkish journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35023658","citation_count":7,"is_preprint":false},{"pmid":"37021575","id":"PMC_37021575","title":"DOCK2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation-Brief Report.","date":"2023","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37021575","citation_count":6,"is_preprint":false},{"pmid":"32369253","id":"PMC_32369253","title":"miR-16 exhibits protective function in LPS-treated cardiomyocytes by targeting DOCK2 to repress cell apoptosis and exert anti-inflammatory effect.","date":"2020","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/32369253","citation_count":6,"is_preprint":false},{"pmid":"35620462","id":"PMC_35620462","title":"Association of a Novel DOCK2 Mutation-Related Gene Signature With Immune in Hepatocellular Carcinoma.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35620462","citation_count":5,"is_preprint":false},{"pmid":"36380073","id":"PMC_36380073","title":"Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36380073","citation_count":4,"is_preprint":false},{"pmid":"39242821","id":"PMC_39242821","title":"Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39242821","citation_count":4,"is_preprint":false},{"pmid":"36836791","id":"PMC_36836791","title":"DOCK2 Mutation and Recurrent Hemophagocytic Lymphohistiocytosis.","date":"2023","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36836791","citation_count":3,"is_preprint":false},{"pmid":"36341455","id":"PMC_36341455","title":"DOCK2 and phosphoinositide-3 kinase δ mediate two complementary signaling pathways for CXCR5-dependent B cell migration.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36341455","citation_count":3,"is_preprint":false},{"pmid":"40153067","id":"PMC_40153067","title":"DOCK2 Deficiency and GATA2 Haploinsufficiency Can Underlie Critical Coronavirus Disease 2019 (COVID-19) Pneumonia.","date":"2025","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40153067","citation_count":3,"is_preprint":false},{"pmid":"39624652","id":"PMC_39624652","title":"Spontaneous Loss-of-Function Dock2 Mutation Alters Murine Colitis Sensitivity and Is a Confounding Variable in Inflammatory Bowel Disease Research.","date":"2019","source":"Crohn's & colitis 360","url":"https://pubmed.ncbi.nlm.nih.gov/39624652","citation_count":3,"is_preprint":false},{"pmid":"39382155","id":"PMC_39382155","title":"Single-Cell Transcriptomics Reveals a Pivotal Role of DOCK2 in Sjögren Disease.","date":"2024","source":"ACR open rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/39382155","citation_count":2,"is_preprint":false},{"pmid":"39603464","id":"PMC_39603464","title":"DOCK2 deficiency alleviates neuroinflammation and affords neuroprotection after spinal cord injury.","date":"2024","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39603464","citation_count":2,"is_preprint":false},{"pmid":"39347442","id":"PMC_39347442","title":"Correction to: Spontaneous Loss-of-Function Dock2 Mutation Alters Murine Colitis Sensitivity and Is a Confounding Variable in Inflammatory Bowel Disease Research.","date":"2024","source":"Crohn's & colitis 360","url":"https://pubmed.ncbi.nlm.nih.gov/39347442","citation_count":2,"is_preprint":false},{"pmid":"40510337","id":"PMC_40510337","title":"DOCK2 protects against bacterial sepsis by constraining T helper 1 response.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40510337","citation_count":1,"is_preprint":false},{"pmid":"40101338","id":"PMC_40101338","title":"Dock2 deficiency reveals abnormal activation and differentiation of T cells under the physiological condition.","date":"2025","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40101338","citation_count":1,"is_preprint":false},{"pmid":"41369116","id":"PMC_41369116","title":"DOCK2 in Disease: Emerging Insights and Research Advances.","date":"2025","source":"Immunological investigations","url":"https://pubmed.ncbi.nlm.nih.gov/41369116","citation_count":1,"is_preprint":false},{"pmid":"41836556","id":"PMC_41836556","title":"The PTBP1-EZH2-DOCK2 axis promotes M1 microglial polarization and exacerbates neuronal apoptosis following spinal cord injury.","date":"2026","source":"Journal of orthopaedic translation","url":"https://pubmed.ncbi.nlm.nih.gov/41836556","citation_count":1,"is_preprint":false},{"pmid":"41371223","id":"PMC_41371223","title":"The TCR-SUB1-DOCK2 axis promotes autoimmunity by driving pathogenic CD4+ T cell tissue infiltration.","date":"2025","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/41371223","citation_count":0,"is_preprint":false},{"pmid":"41268550","id":"PMC_41268550","title":"DOCK2 as a novel CD11c ligand in neutrophils to regulate reactive oxygen species production.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41268550","citation_count":0,"is_preprint":false},{"pmid":"37577614","id":"PMC_37577614","title":"DOCK2-deficiency causes defects in anti-viral T cell responses and poor control of herpes simplex virus infection.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37577614","citation_count":0,"is_preprint":false},{"pmid":"41654261","id":"PMC_41654261","title":"Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses.","date":"2026","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41654261","citation_count":0,"is_preprint":false},{"pmid":"41534628","id":"PMC_41534628","title":"Temporal Proteomic and Phosphoproteomic Profiling Deciphers Molecular Dynamics of Acute-to-Chronic Kidney Disease After Ischemia-Reperfusion Injury, With Dock2 Emerging as a Key Regulator.","date":"2026","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/41534628","citation_count":0,"is_preprint":false},{"pmid":"42020880","id":"PMC_42020880","title":"Dock2 Protects Colitis by Facilitating Akkermansia Colonization via Suppressing IL-22-Reg3 Activity.","date":"2026","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/42020880","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50437,"output_tokens":10148,"usd":0.151765,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20628,"output_tokens":6606,"usd":0.134145,"stage2_stop_reason":"end_turn"},"total_usd":0.28591,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"DOCK2 is essential for lymphocyte chemotaxis: DOCK2-deficient mice show abolished chemokine-induced Rac activation and actin polymerization in T and B lymphocytes, establishing DOCK2 as the central Rac GEF mediating cytoskeletal reorganization downstream of chemokine receptors in lymphocytes.\",\n      \"method\": \"DOCK2 knockout mouse model; Rac activation assay; actin polymerization assay; chemotaxis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype (abolished Rac activation and actin polymerization), replicated across multiple cell types and assays, landmark paper widely confirmed by subsequent work\",\n      \"pmids\": [\"11518968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"DOCK2 (originally KIAA0209) binds to and activates Rac1, similar to DOCK180, but unlike DOCK180 it does not bind CrkII adaptor, indicating hematopoietic-specific Rac regulation independent of focal adhesion signaling.\",\n      \"method\": \"Pulldown/binding assay; Rac1 activation assay; expression analysis in tissue panels\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, pulldown and activation assay, confirmed by subsequent studies; initial characterization paper\",\n      \"pmids\": [\"10559471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DOCK2 associates with ELMO1 through its SH3 domain, and this DOCK2-ELMO1 interaction is required for DOCK2-mediated Rac activation and actin polymerization; a DOCK2 mutant lacking the ELMO1-binding region fails to activate Rac or polymerize actin.\",\n      \"method\": \"Co-immunoprecipitation; DOCK2 domain deletion mutants; Rac activation assay; actin polymerization assay in T-hybridoma cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays plus loss-of-function mutant with defined mechanistic readout, replicated and extended by structural studies\",\n      \"pmids\": [\"12829596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DOCK2 is essential for TCR-mediated Rac activation and immunological synapse formation; DOCK2-deficient T cells show severely impaired antigen-induced translocation of TCR and lipid rafts (but not PKC-θ or LFA-1) to the APC interface, leading to reduced T cell proliferation.\",\n      \"method\": \"DOCK2 knockout T cells; immunofluorescence of immunological synapse components; antigen-specific proliferation assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with specific mechanistic dissection of synapse component translocation using multiple markers\",\n      \"pmids\": [\"12871644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HIV-1 Nef binds the DOCK2-ELMO1 complex (identified by mass spectrometry from T cells) and Rac, and activates Rac by binding this complex; this interaction underlies Nef-mediated inhibition of T cell chemotaxis and promotion of T cell activation.\",\n      \"method\": \"Proteomic purification of Nef-associated complex; mass spectrometry identification; Rac activation assay; chemotaxis assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — near-homogeneity purification + MS identification of DOCK2-ELMO1-Rac complex, functional validation by Rac activation and chemotaxis assays in a single rigorous study\",\n      \"pmids\": [\"14737186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DOCK2 mediates efficient lymphocyte migration in a largely PI3K-independent manner; a residual PI3K-dependent migration pathway exists (PI3Kγ in T cells, other PI3K isoforms in B cells). DOCK2 is required for integrin activation in B cells but not T cells during chemokine-triggered responses.\",\n      \"method\": \"DOCK2-/- and PI3Kγ-/- mouse models; in vitro adhesion assays; intravital microscopy of lymphoid organ vasculature\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using double-KO mice combined with intravital microscopy and multiple adhesion assays\",\n      \"pmids\": [\"15357953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DOCK2 regulates motility and polarity during neutrophil chemotaxis by activating both Rac1 and Rac2; DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a PI3K-dependent manner, enabling polarized accumulation of F-actin and PIP3.\",\n      \"method\": \"DOCK2-/- neutrophils; Rac1/Rac2 activation assays; live-cell imaging of PIP3 and F-actin localization; translocation assay with PI3K inhibition\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO plus live imaging identifying PIP3-dependent membrane translocation as mechanism; multiple orthogonal readouts\",\n      \"pmids\": [\"16943182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DOCK2 is required for T cell receptor-mediated phosphorylation of the microtubule-destabilizing protein stathmin and for lysosomal trafficking and degradation of IL-4Rα, thereby controlling Th2 lineage commitment by preventing sustained IL-4R signaling.\",\n      \"method\": \"DOCK2-/- mice; phosphorylation assay for stathmin; IL-4Rα surface expression and lysosomal trafficking assays; Th2 differentiation analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple mechanistic readouts (stathmin phosphorylation, receptor trafficking, cytokine signaling) in a single focused study\",\n      \"pmids\": [\"17767160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DOCK2 (and to a lesser extent PI3Kγ) is required for interstitial T and B cell motility within peripheral lymph nodes and for S1P-triggered lymphocyte migration and egress from lymph nodes, as established by multiphoton intravital microscopy.\",\n      \"method\": \"Multiphoton intravital microscopy of DOCK2-/- and PI3Kγ-/- mouse PLNs; S1P-induced migration assay; F-actin and PKB phosphorylation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct intravital imaging of KO mice plus in vitro mechanistic assays, multiple signaling readouts\",\n      \"pmids\": [\"17325199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DOCK2 is required for Rac activation and chemotaxis of plasmacytoid dendritic cells (pDCs) but not myeloid dendritic cells, indicating that pDCs and mDCs use distinct molecules to activate Rac during chemotaxis.\",\n      \"method\": \"DOCK2-/- mouse; Rac activation assay in pDCs and mDCs; chemotaxis assay; adoptive transfer experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with Rac activation assay, chemotaxis assay, and in vivo adoptive transfer validation\",\n      \"pmids\": [\"18198348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DOCK2 is essential for TLR7- and TLR9-mediated IFN-α induction in plasmacytoid dendritic cells: nucleic acid ligands induce Rac activation through a TLR-independent, DOCK2-dependent mechanism; this Rac activation drives IKK-α phosphorylation and IRF-7 nuclear translocation required for IFN-α production.\",\n      \"method\": \"DOCK2-/- pDCs; Rac activation assay; IKK-α phosphorylation assay; IRF-7 nuclear translocation assay; dominant-negative Rac expression in wild-type pDCs\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO plus dominant-negative Rac rescue, multiple orthogonal mechanistic readouts (Rac, IKKα, IRF7)\",\n      \"pmids\": [\"20231379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The inflammasome adaptor ASC controls mRNA stability and expression of DOCK2 (independently of NLRP3 or caspase-1); ectopic DOCK2 expression in ASC-deficient cells restores Rac-mediated actin polymerization, antigen uptake, and chemotaxis, placing DOCK2 downstream of ASC in adaptive immune cell function.\",\n      \"method\": \"ASC-/- mice; genome-wide mRNA stability analysis; DOCK2 retroviral rescue experiments; Rac activation, actin polymerization, antigen uptake, and chemotaxis assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO plus rescue experiment with multiple orthogonal functional readouts; identifies ASC as upstream regulator of DOCK2 expression\",\n      \"pmids\": [\"21892172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the DOCK2-ELMO1 N-terminal complex (2.1 Å) reveals that the C-terminal Pro-rich tail of ELMO1 winds around the SH3 domain of DOCK2 forming an intermolecular five-helix bundle; ELMO1 binding relieves DOCK2 autoinhibition (mediated by interaction between its ELMO-interacting region and DHR-2 domain), and DOCK2 binding simultaneously relieves ELMO1 autoinhibition to permit RhoG binding and membrane localization.\",\n      \"method\": \"X-ray crystallography (2.1 Å); mutagenesis; domain binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation; identifies autoinhibition mechanism and mutual relief upon complex formation\",\n      \"pmids\": [\"22331897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CPYPP (4-[3'-(2''-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione) binds reversibly to the DOCK2 DHR-2 catalytic domain and inhibits its GEF activity in vitro; in lymphocytes, CPYPP blocks both chemokine receptor- and antigen receptor-mediated Rac activation, chemotaxis, and T cell activation.\",\n      \"method\": \"In vitro GEF activity assay; compound binding assay to DHR-2; Rac activation assay in lymphocytes; chemotaxis and T cell activation assays\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with defined binding to catalytic domain plus cellular functional assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22520755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK2 dimerization via lobe A of the DHR-2 domain is required for effective Rac activation during cell migration; the lobe A deletion mutant retains in vitro GEF activity but fails to activate Rac effectively at the plasma membrane, as shown by FRET analysis, indicating dimerization enables efficient Rac engagement in vivo.\",\n      \"method\": \"DOCK2 lobe A deletion and point mutants; FRET analysis; Rac activation assay; motility and polarity assays in thymoma cells and primary T cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro GEF assay + FRET live-cell imaging + loss-of-function mutants in primary cells; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23050005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOCK2 associates with CrkL (a hematopoietic-specific adaptor) through two separate regions of DOCK2 binding the CrkL SH3 domain; CrkL-induced Rac1 activation is inhibited by a dominant-negative DOCK2 mutant; DOCK2 also associates with Vav GEF in Jurkat cells, suggesting a CrkL-DOCK2-Vav complex regulates Rac1 in leukocytes.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro; Rac1 activation assay; immunocytochemistry colocalization; stable DOCK2 mutant expression in Jurkat cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and Rac activation assay, single lab, multiple binding partners identified\",\n      \"pmids\": [\"12393632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOCK2 associates with the CD3ζ subunit of the TCR complex in Jurkat cells and activates Rac2; DOCK2-mediated Rac2 activation enhances IL-2 promoter transcriptional activity, and dominant-negative Rac2 suppresses this effect.\",\n      \"method\": \"Co-immunoprecipitation; Rac2 activation assay; IL-2 promoter-luciferase reporter assay; dominant-negative Rac2 expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus activation assay plus reporter assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"12176041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOCK2 is required for NK cell-mediated cytotoxicity: DOCK2-deficient NK cells fail to form lytic synapses due to almost complete loss of NKG2D-mediated Rac activation, despite normal conjugate formation with target cells; selective abrogation of DOCK2 GEF activity recapitulates this defect.\",\n      \"method\": \"DOCK2-/- NK cells; in vitro leukemia cell killing assay; in vivo MHC class I-deficient bone marrow rejection model; lytic synapse formation assay; Rac activation assay; GEF-dead DOCK2 mutant\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO plus GEF-dead mutant; in vitro and in vivo killing assays plus mechanistic Rac activation and synapse formation assays\",\n      \"pmids\": [\"23719299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Elmo1, but not Elmo2, constitutively interacts with Dock2 in primary T lymphocytes; Elmo1 deficiency reduces Dock2 protein levels ~4-fold by promoting Dock2 polyubiquitination and proteasomal degradation, while Elmo1 overexpression inhibits Dock2 ubiquitination; Elmo1 interaction is required for Dock2-dependent Rac activation and chemotaxis.\",\n      \"method\": \"Elmo1-/- mice; Co-IP in primary T cells; ubiquitination assay; proteasome inhibitor rescue; transfection of Elmo1 mutants; Rac activation and chemotaxis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, proteasome rescue, mutant rescue) in primary T cells from KO mice\",\n      \"pmids\": [\"24821968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of DOCK2-ELMO1 alone and as a ternary complex with RAC1 show that the binary complex adopts a closed auto-inhibited conformation; conformational change of ELMO1 to an open state exposes RAC1 binding sites on DOCK2-DHR2 and binding sites for RHOG and BAI GPCRs on ELMO1; upstream effectors including DOCK2 and ELMO1 phosphorylation destabilize the auto-inhibited state.\",\n      \"method\": \"Cryo-EM structure determination; crystal structure of RHOG-ELMO2-RBD complex; functional mutagenesis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM and crystal structures with functional mutagenesis; independent structural validation of autoinhibition mechanism previously identified biochemically\",\n      \"pmids\": [\"32651375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a induces ROR1 to recruit DOCK2 via the cytoplasmic proline-rich domain (PRD) of ROR1, specifically requiring Pro808; this ROR1-DOCK2 interaction activates Rac1/2 in CLL cells and is required for Wnt5a-driven CLL cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation; ROR1 truncation and point mutants; DOCK2 siRNA knockdown; Rac1/2 activation assay; proliferation assay; cirmtuzumab blocking\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping and single-residue mutagenesis (P808A) plus functional Rac activation and proliferation assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29678828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cholesterol sulfate (CS) binds to the catalytic DHR-2 domain of DOCK2 and suppresses its GEF activity, inhibiting DOCK2-mediated Rac activation and leukocyte migration; CS is the most abundantly produced in the Harderian gland via SULT2B1b/a sulfotransferases, and Sult2b1 knockout mice show augmented ocular surface inflammation.\",\n      \"method\": \"In vitro GEF activity assay; CS binding assay to DOCK2 DHR-2; mass spectrometric quantification of CS; Sult2b1 knockout mice; ocular inflammation model; leukocyte migration assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic inhibition assay with defined binding to catalytic domain, in vivo KO validation, and identification of endogenous inhibitor source; multiple orthogonal methods\",\n      \"pmids\": [\"30065028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PIP3-dependent recruitment and activation of DOCK2 at the plasma membrane is required for sustained growth of BCR microclusters through F-actin cytoskeleton remodeling; DOCK2 deficiency disrupts B cell immunological synapse structure.\",\n      \"method\": \"DOCK2-/- B cells; PI3K inhibition; live-cell imaging of BCR microclusters; F-actin assay; B cell immunological synapse imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO plus PI3K inhibition with live imaging and F-actin mechanistic readouts in primary B cells\",\n      \"pmids\": [\"29186690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DOCK2 is required for BCR-mediated Rac activation in B cells; DOCK2-deficient B cells show defects in B cell spreading, sustained BCR microcluster growth, and plasma cell differentiation both in vitro and in vivo, implicating the DOCK2-Rac axis in IgG antibody responses.\",\n      \"method\": \"DOCK2-/- B cells; conditional DOCK2 knockout (B cell lineage); Rac activation assay; B cell spreading assay; BCR microcluster imaging; plasma cell differentiation assay in vitro and in vivo; adoptive transfer\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus global KO with multiple in vitro and in vivo functional assays and mechanistic readouts\",\n      \"pmids\": [\"29503648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DOCK2 co-immunoprecipitates with wild-type FLT3 and FLT3/ITD in leukemia cells; DOCK2 knockdown selectively reduces proliferation and colony formation in leukemia cells with elevated FLT3 activity and sensitizes FLT3/ITD cells to cytarabine.\",\n      \"method\": \"Mass spectrometry screen for FLT3-interacting proteins; co-immunoprecipitation; shRNA knockdown; proliferation, colony formation, and cell survival assays; mouse xenograft model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS identification plus Co-IP confirmed interaction; functional KD assays in cell lines and xenograft; single lab\",\n      \"pmids\": [\"27748370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"After fungal stimulation, SYK phosphorylates DOCK2 at tyrosine residues Y985 and Y1405, promoting recruitment and activation of Rac GTPases, which increases ROS production and downstream antifungal signaling in macrophages.\",\n      \"method\": \"Phosphorylation assay; site-directed mutagenesis of DOCK2 tyrosine residues; Rac activation assay; ROS production assay; DOCK2-/- macrophages; in vivo fungal infection model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — identification of specific phosphorylation sites by mutagenesis with mechanistic Rac activation and ROS assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35079145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DOCK2 (together with SOS1 and ARHGEF1) mediates JAK-dependent CXCL12-induced LFA-1 activation and Rac1 activation in human primary T lymphocytes; DOCK2 is tyrosine-phosphorylated upon chemokine signaling in a JAK- and pertussis toxin-sensitive manner.\",\n      \"method\": \"DOCK2 siRNA knockdown; LFA-1 adhesion assay under flow; Rac1 activation assay; tyrosine phosphorylation assay; JAK inhibitor treatment; pertussis toxin pretreatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional adhesion and Rac activation assays in primary human T cells; identifies JAK-DOCK2 phosphorylation axis; single lab\",\n      \"pmids\": [\"27986909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DOCK2 regulates MRGPRB2-mediated mast cell degranulation through Rac activation and PAK1 phosphorylation; DOCK2-deficient mast cells show impaired MRGPRB2-mediated Rac activation and PAK1 phosphorylation while calcium influx and other signaling molecules are unaffected.\",\n      \"method\": \"DOCK2-/- mice; mast cell degranulation assay (compound 48/80, ciprofloxacin); Rac activation assay; PAK1 phosphorylation assay; calcium flux assay; small-molecule DOCK2 inhibitors; systemic and cutaneous anaphylaxis models\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO plus pharmacological inhibition with mechanistic dissection separating Rac-PAK1 from calcium pathway; multiple orthogonal methods and in vivo confirmation\",\n      \"pmids\": [\"36804596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cholesterol sulfate synthesized by SULT2B1 in tumor cells suppresses DOCK2 enzymatic GEF activity in T cells, promoting CD8+ T cell exhaustion in the HCC tumor microenvironment; tolazamide reverses DOCK2 inactivation-mediated T cell exhaustion.\",\n      \"method\": \"Quasi-targeted metabolomics; mass spectrometry; mass cytometry (CyTOF); DOCK2 GEF activity assay; flow cytometry; mouse HCC models; virtual screening and molecular docking\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GEF activity assay plus multiple orthogonal cell biology methods; single lab; extends the cholesterol sulfate-DOCK2 inhibition finding to the tumor microenvironment\",\n      \"pmids\": [\"36626623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DOCK2 generates characteristic spatiotemporal patterns of Rac activity (visualized by live TIRF-FRET imaging in primary neutrophils) that are specifically required for neutrophil polarization, random migration, chemotaxis speed and turning, and rapid phagocytosis; Dock2 deficiency abolishes these spatially distinct Rac pools at leading edges.\",\n      \"method\": \"Live TIRF-FRET imaging with Rac-FRET reporter mice; DOCK2-/-, Tiam1-/-, Prex1-/-Vav1-/- neutrophils; polarization, migration velocity, chemotaxis, and phagocytosis assays; in vivo peritonitis model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct live-cell FRET imaging of Rac activity pools combined with multiple KO comparisons and in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37383235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The transcription factor SUB1, induced by the TCR-IRF4 axis, directly trans-activates DOCK2 transcription by forming liquid-liquid phase separation condensates that open chromatin at the Dock2 locus and partners with JUNB to amplify Dock2 expression; conditional Sub1 deletion reduces DOCK2 expression, impairs Rac-dependent actin polymerization and T cell motility, and prevents experimental autoimmune encephalomyelitis.\",\n      \"method\": \"Conditional T cell-specific Sub1 KO mice; chromatin accessibility assay; ChIP; phase separation assay; transcriptional reporter assay; DOCK2 expression assay; Rac activation; actin polymerization; EAE model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (ChIP, phase separation, reporter assay, in vivo KO) in a single rigorous study identifying the TCR-SUB1-DOCK2 transcriptional axis\",\n      \"pmids\": [\"41371223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD11c (integrin αX) physically associates with DOCK2 intracellularly in neutrophils (confirmed by co-immunoprecipitation and proteomics); CD11c-deficient neutrophils show reduced DOCK2 phosphorylation and impaired Rac activation, leading to selective defects in ROS/NADPH oxidase activity without affecting phagocytosis.\",\n      \"method\": \"Phosphoproteomic profiling of CD11c-/- neutrophils; co-immunoprecipitation + proteomics; ROS production assay; phagocytosis assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus proteomics plus functional assays; single lab; identifies CD11c as upstream regulator of DOCK2 phosphorylation and Rac activity in neutrophils\",\n      \"pmids\": [\"41268550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inhibitory peptides discovered by T7 phage display bind the DOCK2 catalytic domain and block DOCK2-Rac1 protein-protein interaction at nanomolar concentrations; cell-penetrating peptide conjugation enables intracellular delivery and inhibition of B cell migration (IC50 ~120 nM).\",\n      \"method\": \"Random peptide T7 phage display; in vitro DOCK2 GEF inhibition assay; cell migration assay; cellular internalization assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro GEF inhibition assay with defined binding plus cell migration assay; single lab, focused on drug development\",\n      \"pmids\": [\"28039053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DOCK2 inhibition with CPYPP increased severity of SARS-CoV-2 pneumonia in a Syrian hamster model, characterized by impaired macrophage recruitment and dysregulated type I interferon responses, demonstrating that DOCK2 function is required for macrophage-mediated antiviral immunity.\",\n      \"method\": \"DOCK2 inhibitor (CPYPP) treatment in Syrian hamster SARS-CoV-2 model; viral load measurement; macrophage recruitment assay; type I IFN response assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition in in vivo infection model with defined cellular and molecular readouts; single study but in a relevant in vivo system\",\n      \"pmids\": [\"35940203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DOCK2 promotes TGF-β-induced fibroblast-to-myofibroblast transition (FMT) in lung fibroblasts; TGF-β upregulates DOCK2 expression via both Smad3 and ERK pathways and also stabilizes DOCK2 protein; DOCK2 knockdown attenuates α-SMA, collagen-1, and fibronectin induction; DOCK2-/- mice are protected from bleomycin-induced pulmonary fibrosis.\",\n      \"method\": \"DOCK2 siRNA knockdown in primary human lung fibroblasts; Smad3/ERK inhibitors; DOCK2-/- mouse bleomycin model; Western blot for FMT markers\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with pathway inhibitors plus in vivo KO model; single lab; identifies Smad3/ERK-DOCK2-FMT axis\",\n      \"pmids\": [\"35584329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DOCK2 interacts with transcription factor FoxM1 and enhances FoxM1 binding to mesenchymal marker gene promoters, promoting mesenchymal marker gene transcription and EMT in airway epithelial cells downstream of TGF-β1 stimulation.\",\n      \"method\": \"DOCK2-FoxM1 co-immunoprecipitation; ChIP assay for FoxM1 promoter binding; DOCK2 KD and overexpression; TGF-β1-induced EMT assay; DOCK2-/- HDM-induced asthma mouse model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP for mechanistic pathway placement; in vivo KO validation; single lab\",\n      \"pmids\": [\"36883952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DOCK2-mediated Rac activation is required for TLR4-induced inflammatory responses in macrophages; LPS induces Rac activation through a TLR4-independent, DOCK2-dependent mechanism; DOCK2-Rac signaling controls IKKβ activation and NF-κB nuclear translocation for inflammatory cytokine release.\",\n      \"method\": \"Ad-shDOCK2 macrophages; Rac activation assay; IKKβ phosphorylation assay; NF-κB nuclear translocation assay; CPYPP pharmacological inhibition; LPS-induced ALI mouse model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD plus Rac inhibitor with mechanistic signaling readouts and in vivo pharmacological confirmation; single lab\",\n      \"pmids\": [\"33382969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DOCK2 is expressed specifically in microglia in the brain and regulates microglial innate immunity (cytokine secretion, phagocytosis, paracrine neurotoxicity) independently of COX2 induction; DOCK2 links to prostaglandin E2 receptor EP2 signaling in the brain.\",\n      \"method\": \"Immunohistochemistry of human AD brain; DOCK2-/- microglial functional assays (cytokine, phagocytosis, neurotoxicity); EP2-DOCK2 pathway analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KO functional assays in microglia with multiple readouts; single lab; localization established by IHC with functional follow-up\",\n      \"pmids\": [\"19729484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt5a induces ERK1/2 phosphorylation and CLL cell proliferation via ROR1/DOCK2-dependent pathway; DOCK2 siRNA knockdown blocks Wnt5a-induced ERK1/2 phosphorylation, and ROR1P808A (unable to recruit DOCK2) fails to mediate these effects; ibrutinib cannot inhibit this Wnt5a-ROR1-DOCK2-ERK1/2 axis.\",\n      \"method\": \"DOCK2 siRNA; ROR1 mutants (ΔPRD, P808A); ERK1/2 phosphorylation assay; DOCK2 phosphorylation assay; CLL cell proliferation assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD plus domain mutants with phosphorylation and proliferation readouts; single lab; extends prior ROR1-DOCK2 finding\",\n      \"pmids\": [\"33097837\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOCK2 is a hematopoietic cell-specific, atypical Rac-GEF that lacks a Dbl-homology domain but mediates GTP-GDP exchange for Rac1 and Rac2 via its DHR-2 (CZH2) catalytic domain; it forms an obligate complex with ELMO1 through its SH3 domain (structurally characterized by both X-ray crystallography and cryo-EM), with ELMO1 binding mutually relieving autoinhibition in both partners and preventing proteasomal degradation of DOCK2; PIP3 recruits DOCK2 to the plasma membrane in a PI3K-dependent manner; once activated, DOCK2-Rac signaling drives actin polymerization, lamellipodia formation, cell polarization, immunological synapse formation, BCR microcluster growth, lytic granule polarization, and type I IFN induction via IKKα-IRF7 in plasmacytoid dendritic cells; upstream activators include chemokine receptors, TCR/CD3ζ, BCR, FLT3, ROR1 (via Wnt5a), NKG2D, MRGPRB2, SYK (phosphorylating Y985/Y1405 after fungal stimulation), CD11c, and the transcription factor SUB1 (which opens the Dock2 chromatin locus downstream of TCR-IRF4); endogenous inhibition is provided by cholesterol sulfate binding to the DHR-2 domain; small-molecule inhibitor CPYPP and peptide inhibitors targeting the DOCK2-Rac1 interface block its catalytic activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOCK2 is a hematopoietic cell-enriched, atypical guanine nucleotide exchange factor that serves as the central activator of Rac GTPases (Rac1 and Rac2) driving actin-dependent cytoskeletal reorganization throughout the immune system [#0, #1, #6]. In lymphocytes, DOCK2 is required for chemokine-induced Rac activation and actin polymerization, and its loss abolishes chemotaxis [#0]. DOCK2 functions as an obligate partner of ELMO1: it binds ELMO1 through its SH3 domain, and this association is required for Rac activation and actin polymerization, mutually relieving autoinhibition in both proteins and protecting DOCK2 from polyubiquitination and proteasomal degradation [#2, #12, #18, #19]. Catalysis is executed by the DHR-2 domain, whose activity additionally requires lobe A-mediated dimerization for efficient Rac engagement at the membrane [#13, #14]. DOCK2 is recruited to the plasma membrane and leading edge by PIP3 in a PI3K-dependent manner, generating spatially defined pools of active Rac that pattern cell polarization, migration, and phagocytosis [#6, #22, #29]. Through this axis DOCK2 controls immunological synapse formation and TCR/lipid-raft translocation in T cells [#3], BCR microcluster growth and plasma cell differentiation in B cells [#22, #23], lytic synapse formation in NK cells [#17], mast cell degranulation via Rac-PAK1 [#27], and TLR7/9-driven IFN-\\u03b1 induction in plasmacytoid dendritic cells through Rac-dependent IKK\\u03b1 phosphorylation and IRF-7 nuclear translocation [#10]. DOCK2 is engaged by diverse upstream receptors and kinases, including the CD3\\u03b6 chain of the TCR [#16], SYK (which phosphorylates Y985/Y1405 after fungal stimulation) [#25], FLT3 [#24], ROR1 downstream of Wnt5a [#20], and CD11c [#31], and its expression is transcriptionally controlled by the TCR-IRF4-SUB1 axis [#30]. Endogenous inhibition is provided by cholesterol sulfate binding to the DHR-2 domain, a mechanism exploited in the tumor microenvironment to drive CD8+ T cell exhaustion [#21, #28], and DOCK2 catalysis is pharmacologically blocked by the small molecule CPYPP and by peptides targeting the DOCK2-Rac1 interface [#13, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that DOCK2 is a Rac1 activator distinct from focal-adhesion DOCK180 defined it as a candidate hematopoietic-specific Rac regulator.\",\n      \"evidence\": \"pulldown/binding and Rac1 activation assays with tissue expression analysis\",\n      \"pmids\": [\"10559471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic mechanism or domain responsible for exchange defined\", \"No in vivo phenotype\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic deletion showed DOCK2 is the central Rac GEF coupling chemokine receptors to cytoskeletal remodeling in lymphocytes, settling its physiological role.\",\n      \"evidence\": \"DOCK2 knockout mice with Rac activation, actin polymerization, and chemotaxis assays in T and B cells\",\n      \"pmids\": [\"11518968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-to-DOCK2 coupling mechanism unresolved\", \"Membrane recruitment mechanism not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of CD3\\u03b6 and CrkL/Vav associations placed DOCK2 within antigen- and adaptor-receptor signaling complexes that activate Rac2 and drive IL-2 transcription.\",\n      \"evidence\": \"co-immunoprecipitation, Rac activation, and IL-2 promoter reporter assays in Jurkat cells\",\n      \"pmids\": [\"12176041\", \"12393632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line Co-IPs without reciprocal validation in primary cells\", \"Direct vs. indirect binding not distinguished\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the ELMO1 interaction to the DOCK2 SH3 domain and showing it is essential for Rac activation defined the obligate DOCK2-ELMO1 functional unit.\",\n      \"evidence\": \"Co-IP, domain-deletion mutants, and Rac/actin assays in T-hybridoma cells; KO T cells for synapse formation\",\n      \"pmids\": [\"12829596\", \"12871644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SH3-ELMO1 binding not yet defined\", \"Whether ELMO1 affects DOCK2 stability not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defining a PI3K-largely-independent migration role and identifying HIV-1 Nef hijacking of the DOCK2-ELMO1-Rac complex clarified both physiological and pathogen-manipulated activation routes.\",\n      \"evidence\": \"double-KO mice with intravital microscopy; proteomic purification and MS of the Nef-associated complex with functional Rac/chemotaxis assays\",\n      \"pmids\": [\"15357953\", \"14737186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of PI3K vs PI3K-independent recruitment unresolved\", \"Direct Nef-DOCK2 contact surface not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Live imaging established that PIP3 recruits DOCK2 to the leading edge in a PI3K-dependent manner, providing the spatial mechanism for polarized Rac activation in neutrophils.\",\n      \"evidence\": \"DOCK2-/- neutrophils with Rac1/Rac2 assays, live-cell PIP3/F-actin imaging, and PI3K-inhibited translocation assays\",\n      \"pmids\": [\"16943182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid-binding determinant on DOCK2 not mapped\", \"How dual Rac1/Rac2 selectivity is set is unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing DOCK2 controls stathmin phosphorylation, IL-4R\\u03b1 trafficking, and lymphocyte interstitial motility/egress extended its role beyond chemotaxis into receptor trafficking and Th lineage decisions.\",\n      \"evidence\": \"DOCK2-/- mice with stathmin phosphorylation, receptor trafficking, Th2 differentiation assays, and multiphoton intravital microscopy\",\n      \"pmids\": [\"17767160\", \"17325199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link from Rac to stathmin phosphorylation not established\", \"Mechanism of IL-4R\\u03b1 lysosomal targeting unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cell-type comparisons revealed DOCK2 is required for Rac activation in plasmacytoid but not myeloid dendritic cells, demonstrating lineage-specific Rac-GEF wiring.\",\n      \"evidence\": \"DOCK2-/- pDC vs mDC Rac activation, chemotaxis, and adoptive transfer assays\",\n      \"pmids\": [\"18198348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the mDC Rac GEF not addressed\", \"Basis of pDC-specific dependence unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking DOCK2-Rac to IKK\\u03b1 phosphorylation and IRF-7 nuclear translocation defined the signaling route from TLR7/9 nucleic-acid sensing to type I IFN production in pDCs.\",\n      \"evidence\": \"DOCK2-/- pDCs with Rac, IKK\\u03b1 phosphorylation, IRF-7 translocation assays and dominant-negative Rac rescue\",\n      \"pmids\": [\"20231379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nucleic acid sensing activates DOCK2 TLR-independently is unresolved\", \"Direct Rac-to-IKK\\u03b1 link not biochemically defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying ASC as a controller of DOCK2 mRNA stability placed DOCK2 expression under inflammasome-adaptor regulation independent of caspase-1.\",\n      \"evidence\": \"ASC-/- mice, genome-wide mRNA stability analysis, and DOCK2 retroviral rescue of Rac/actin/chemotaxis defects\",\n      \"pmids\": [\"21892172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which ASC stabilizes DOCK2 mRNA unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystallography, dimerization analysis, and a catalytic-domain inhibitor together defined DOCK2's autoinhibition, the structural basis of mutual relief with ELMO1, and the requirement for DHR-2 dimerization in vivo.\",\n      \"evidence\": \"2.1 \\u00c5 crystal structure of DOCK2-ELMO1 with mutagenesis; lobe A deletion mutants with FRET; CPYPP GEF inhibition and cellular assays\",\n      \"pmids\": [\"22331897\", \"23050005\", \"22520755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length conformational dynamics not captured at this stage\", \"How upstream signals trigger the autoinhibition switch not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that DOCK2 GEF activity is required for NKG2D-driven lytic synapse formation extended its Rac-activating role to NK-cell cytotoxicity.\",\n      \"evidence\": \"DOCK2-/- and GEF-dead NK cells with killing, lytic synapse, and Rac activation assays plus in vivo BM rejection model\",\n      \"pmids\": [\"23719299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling of NKG2D to DOCK2 not biochemically mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing ELMO1 prevents DOCK2 polyubiquitination established that complex formation is also a protein-stability mechanism, not merely an activation switch.\",\n      \"evidence\": \"Elmo1-/- mice, Co-IP, ubiquitination assays, proteasome-inhibitor rescue, and mutant rescue in primary T cells\",\n      \"pmids\": [\"24821968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase targeting DOCK2 not identified\", \"Why Elmo2 cannot substitute is unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Receptor-coupling studies and inhibitory-peptide work connected DOCK2 to FLT3 and JAK/chemokine signaling and validated the DOCK2-Rac1 interface as a druggable surface.\",\n      \"evidence\": \"MS/Co-IP with FLT3, shRNA functional assays; siRNA with LFA-1/Rac and phosphorylation assays; phage-display peptide GEF inhibition and migration assays\",\n      \"pmids\": [\"27748370\", \"27986909\", \"28039053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold-mediated FLT3-DOCK2 contact not resolved\", \"JAK phosphosites on DOCK2 not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying cholesterol sulfate as an endogenous DHR-2 inhibitor and ROR1 as a Wnt5a-driven recruiter defined both a physiological brake and an oncogenic activation route for DOCK2.\",\n      \"evidence\": \"in vitro GEF/binding assays, Sult2b1-/- ocular inflammation model; ROR1 P808A mutagenesis with Co-IP and Rac/proliferation assays in CLL\",\n      \"pmids\": [\"30065028\", \"29678828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cholesterol sulfate binding site on DHR-2 not structurally defined\", \"Whether ROR1 recruitment requires ELMO1 not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"B-cell genetics established that PIP3-recruited DOCK2 sustains BCR microcluster growth and is required for plasma cell differentiation and antibody responses.\",\n      \"evidence\": \"DOCK2-/- and conditional KO B cells with PI3K inhibition, microcluster/F-actin imaging, and in vitro/in vivo plasma cell assays\",\n      \"pmids\": [\"29186690\", \"29503648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effectors linking Rac to BCR microcluster stability not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM of binary and RAC1-ternary complexes provided independent structural confirmation of the closed autoinhibited state and how the open ELMO1 conformation exposes RAC1, RHOG, and BAI-GPCR binding sites.\",\n      \"evidence\": \"cryo-EM structures, RHOG-ELMO2-RBD crystal structure, and functional mutagenesis\",\n      \"pmids\": [\"32651375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger ordering of phosphorylation vs membrane recruitment not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extending DOCK2-Rac to innate macrophage signaling showed it controls TLR4-induced IKK\\u03b2/NF-\\u03baB activation and microglial innate immunity, broadening its inflammatory roles.\",\n      \"evidence\": \"shRNA and CPYPP in macrophages with Rac/IKK\\u03b2/NF-\\u03baB assays and ALI model; DOCK2-/- microglia functional assays\",\n      \"pmids\": [\"33382969\", \"19729484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TLR4-independent LPS-induced Rac activation unresolved\", \"Direct Rac-to-IKK\\u03b2 link not biochemically defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying SYK phosphosites (Y985/Y1405) and a CPYPP-revealed antiviral macrophage role defined post-translational activation and protective innate functions of DOCK2.\",\n      \"evidence\": \"site-directed mutagenesis with Rac/ROS assays after fungal stimulation; CPYPP in a hamster SARS-CoV-2 model with macrophage and IFN readouts; TGF-\\u03b2 fibrosis model\",\n      \"pmids\": [\"35079145\", \"35940203\", \"35584329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation couples to DHR-2 conformational change not defined\", \"Fibrosis mechanism (Rac-dependence) not fully dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Studies in mast cells, NK/T tumor immunity, neutrophil Rac patterning, CD11c coupling, and FoxM1-driven EMT mapped DOCK2's reach across degranulation, exhaustion, oxidative burst, and epithelial transcription programs.\",\n      \"evidence\": \"DOCK2-/- mast cells (Rac-PAK1); SULT2B1/cholesterol sulfate HCC models; TIRF-FRET Rac imaging in neutrophils; CD11c-/- phosphoproteomics; DOCK2-FoxM1 Co-IP/ChIP\",\n      \"pmids\": [\"36804596\", \"36626623\", \"37383235\", \"41268550\", \"36883952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear DOCK2-FoxM1 function is Rac-dependent unclear\", \"Mechanism of CD11c-driven DOCK2 phosphorylation not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying the TCR-IRF4-SUB1 axis as a phase-separation-driven transcriptional activator of DOCK2 closed a gap in how DOCK2 expression is induced during T cell activation.\",\n      \"evidence\": \"conditional Sub1 KO mice with chromatin accessibility, ChIP, phase-separation, reporter assays, Rac/actin readouts, and EAE model\",\n      \"pmids\": [\"41371223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUB1 condensates select the Dock2 locus specifically not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream phosphorylation, PIP3 recruitment, and ELMO1-mediated conformational opening are integrated into a single ordered activation switch, and how this is differentially tuned across immune lineages, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified kinetic model integrating membrane, phospho, and conformational inputs\", \"Lineage-specific differences in DOCK2 regulation not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 13, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [10, 16, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 22, 29]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 10, 17, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 16, 20, 25, 36]}\n    ],\n    \"complexes\": [\n      \"DOCK2-ELMO1 complex\"\n    ],\n    \"partners\": [\n      \"ELMO1\",\n      \"RAC1\",\n      \"RAC2\",\n      \"CrkL\",\n      \"CD3Z\",\n      \"ROR1\",\n      \"FLT3\",\n      \"SYK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}