{"gene":"DOCK3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2004,"finding":"MOCA/DOCK3 binds directly to Rac1 and enhances its GTPase activity, leading to activation of c-Jun N-terminal kinase (JNK) and changes in cell morphology. Farnesylated MOCA localized to the plasma membrane showed enhanced Rac1 and JNK activation. Endogenous MOCA concentrates at lamellipodia leading edges and growth cones co-localized with actin filaments.","method":"Co-immunoprecipitation, GTPase activity assay (Rac1 pull-down), overexpression of farnesylated vs. wild-type MOCA, immunofluorescence in cortical neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay, GTPase activity assay, multiple cell morphology readouts, replicated with farnesylated construct and primary neurons","pmids":["14718541"],"is_preprint":false},{"year":2010,"finding":"DOCK3 directly associates with WAVE proteins through its DHR-1 domain. BDNF-TrkB signaling recruits the DOCK3/WAVE1 complex to the plasma membrane, whereupon DOCK3 activates Rac1 and dissociates from the WAVE complex in a phosphorylation-dependent manner, driving axonal outgrowth. Key conserved amino acids in the DHR-2 domain are critical for catalytic GEF activity of DOCK3.","method":"Co-immunoprecipitation, DHR-1/DHR-2 domain mutagenesis, membrane fractionation, in vivo optic nerve regeneration in Dock3 transgenic mice, neurite outgrowth assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mutagenesis identifying catalytic residues, reciprocal co-IP, in vitro and in vivo assays in multiple systems","pmids":["20368433"],"is_preprint":false},{"year":2012,"finding":"DOCK3 binds to and inactivates GSK-3β at the plasma membrane, increasing the non-phosphorylated active form of CRMP-2, which promotes microtubule assembly and axon branching. BDNF induced GSK-3β phosphorylation and CRMP-2 dephosphorylation in hippocampal neurons, and elevated GSK-3β phosphorylation was detected in regenerating axons of Dock3 transgenic mice after optic nerve injury.","method":"Co-immunoprecipitation, phosphorylation assays (Western blot), primary hippocampal neuron culture, in vivo optic nerve crush in Dock3 Tg mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus functional phosphorylation assays in vitro and in vivo in transgenic mice, two orthogonal methods","pmids":["22219288"],"is_preprint":false},{"year":2012,"finding":"DOCK3 forms a ternary complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling to induce neurite outgrowth via Rac1 activation in PC12 cells. Phosphorylation of DOCK3 and its interaction with Elmo are both required for efficient Rac1 activation; membrane recruitment of DOCK3 is also necessary.","method":"Co-immunoprecipitation, Rac1 pull-down (active GTP-bound Rac1 assay), neurite outgrowth assay in PC12 cells, site-directed mutagenesis of phosphorylation sites","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, GTPase activity assay, mutagenesis, functional neurite outgrowth readout, single lab","pmids":["22734669"],"is_preprint":false},{"year":2013,"finding":"DOCK3 directly binds to the intracellular C-terminus domain of NR2B (GluN2B), an NMDA receptor subunit. Overexpression of DOCK3 in transgenic mice decreased NR2B expression in the retina and ameliorated NMDA-induced retinal degeneration. DOCK3 overexpression also suppressed phosphorylation of NR2B in GLAST-KO mice, reducing excitotoxic and oxidative stress-related RGC death.","method":"Co-immunoprecipitation (DOCK3 and NR2B C-terminus), Western blot, in vivo retinal degeneration assay in Dock3 Tg and GLAST KO mice, NMDA injection model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding shown by co-IP, functional validation in multiple transgenic mouse models with quantitative retinal degeneration readouts","pmids":["23852370"],"is_preprint":false},{"year":2013,"finding":"DOCK3 binds to the NR2D C-terminal domain and reduces surface expression of NR2D, thereby protecting retinal ganglion cells from excitotoxicity. NR2D deficiency also attenuates RGC loss in GLAST-deficient mice.","method":"Co-immunoprecipitation (DOCK3 and NR2D C-terminus), surface expression assay, genetic mouse models (NR2D KO × GLAST KO), RGC counting","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding by co-IP, surface expression assay, multiple genetic mouse models with quantitative RGC loss phenotype","pmids":["23641686"],"is_preprint":false},{"year":2008,"finding":"MOCA/DOCK3 functions as a negative regulator of Wnt/β-catenin signaling. MOCA forms a complex with β-catenin and inhibits transcription of Wnt target genes, reduces nuclear β-catenin levels, increases membrane-bound β-catenin levels, and enhances cell-cell adhesion. Epistasis experiments placed MOCA action at the level of reducing nuclear β-catenin.","method":"Functional cDNA library screen in human cells, co-immunoprecipitation (MOCA and β-catenin), Wnt target gene luciferase reporter assay, subcellular fractionation, cell-cell adhesion assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, luciferase reporter, fractionation, and epistasis all in same study; multiple orthogonal methods","pmids":["18716063"],"is_preprint":false},{"year":2012,"finding":"MOCA/DOCK3 is a downstream integrator of neuronal death signals from both familial AD-linked APP mutants and presenilin (PS1/PS2) mutants, in a γ-secretase-independent manner. MOCA links PS-mediated death signals with APP-mediated death signals at a point between Rac1/Cdc42 and ASK1 (apoptosis signal-regulating kinase 1).","method":"Cell death assays with AD mutant constructs (APP, PS1, PS2), epistasis analysis using MOCA overexpression/knockdown, genetic interaction experiments in neuronal cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and cell-based functional assays, single lab, mechanistic placement between Rac1/Cdc42 and ASK1 inferred from knockdown/overexpression","pmids":["22115042"],"is_preprint":false},{"year":2014,"finding":"DOCK3 is a direct target of miR-486 in skeletal muscle. Overexpression of DOCK3 in human myotubes modulates PTEN/AKT signaling (increases PTEN and reduces phosphorylated AKT) and induces apoptosis. In dystrophic mice, miR-486 overexpression decreases DOCK3 levels, reduces PTEN expression, and increases phospho-AKT.","method":"miR-486 target validation (3'UTR luciferase), DOCK3 overexpression in human myotubes, Western blot for PTEN/pAKT, in vivo miR-486 transgenic mice on DMD background","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — target validation, functional overexpression assays, in vivo transgenic model, multiple signaling readouts, independently confirmed in multiple systems","pmids":["24789910"],"is_preprint":false},{"year":2015,"finding":"DOCK3, as a RAC1-GEF, is a target of miR-512-3p in NSCLC cells. Knockdown of DOCK3 inhibited cell adhesion, migration, and invasion, and decreased active RAC1 levels, demonstrating that DOCK3 promotes RAC1 activity and metastatic behaviors in lung cancer cells.","method":"miR-512-3p overexpression, DOCK3 siRNA knockdown, active RAC1 pull-down assay, cell migration/invasion assays in A549 and H1299 cell lines","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active GTPase pull-down, functional migration/invasion assays, knockdown, single lab two orthogonal methods","pmids":["25687035"],"is_preprint":false},{"year":2016,"finding":"DOCK3 acts as a negative regulator of WAVE2 expression by blocking β-catenin nuclear translocation; phospho-Annexin A2 (pY23) promotes DOCK3 expression, and DOCK3 inhibits lamellipodium dynamics and tumor cell movement via suppression of β-catenin/WAVE2 signaling axis.","method":"Co-immunoprecipitation, in vitro kinase assay (Src/CD147/Annexin A2), DOCK3 knockdown, Western blot, cell migration assay, β-catenin subcellular localization","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, knockdown with functional migration readout, single lab","pmids":["26716413"],"is_preprint":false},{"year":2014,"finding":"DOCK3 is expressed in oligodendrocytes, and Dock3 overexpression protects myelin in the corpus callosum and optic nerves in a cuprizone-induced demyelination model. In Dock3 Tg mice, Erk activation is increased, suggesting ERK signaling as part of the Dock3-mediated protective mechanism.","method":"Immunohistochemistry for oligodendrocyte markers, cuprizone demyelination model in Dock3 Tg mice, multifocal electroretinogram, Western blot (pErk)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model, functional visual readout, ERK phosphorylation assay, single lab","pmids":["25165881"],"is_preprint":false},{"year":2015,"finding":"Dock3 expression increases in epileptic brain tissue and models, and Dock3 shRNA knockdown reduces Rac1-GTP levels, decreases severity of status epilepticus, reduces spontaneous recurrent seizures, and increases latency in a kindling model, placing Dock3 upstream of Rac1 in epileptogenesis.","method":"shRNA knockdown of Dock3 in lithium-pilocarpine and pentylenetetrazole kindling mouse models, active Rac1 pull-down, behavioral seizure scoring","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with behavioral readout plus active Rac1 measurement, single lab","pmids":["26319681"],"is_preprint":false},{"year":2019,"finding":"DOCK3 missense variants in or adjacent to the DHR-2 domain significantly reduce Rac1 GEF activity compared to wild-type DOCK3, confirming that the DHR-2 domain is critical for Rac1 activation and that loss-of-function of this activity underlies the neurodevelopmental phenotype.","method":"Site-directed mutagenesis of patient missense variants, Rac1 pull-down (active GTP-bound Rac1) assay in transfected cells, protein structural modeling","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro mutagenesis with GTPase activity assay, single lab, limited patient numbers","pmids":["30976111"],"is_preprint":false},{"year":2020,"finding":"DOCK3 is a dosage-sensitive modulator of skeletal muscle function. Haploinsufficiency of Dock3 in DMD mice improved dystrophic muscle pathologies, but complete knockout worsened muscle function. Dock3 KO myoblasts are defective in myogenic differentiation, with transcriptomic analyses revealing decreased myogenic factors.","method":"Dock3 global knockout mice crossed with mdx dystrophic mice, muscle function tests, myoblast differentiation assays, RNA-seq transcriptomics","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout in two disease-relevant models, functional muscle assays, transcriptomics, single lab","pmids":["32766788"],"is_preprint":false},{"year":2023,"finding":"DOCK3 directly interacts with SORBS1 through its C-terminal domain in skeletal muscle. Conditional muscle-specific Dock3 knockout (mKO) mice display hyperglycemia, increased fat mass, impaired myofiber regeneration, and metabolic dysfunction, establishing a role for DOCK3 in skeletal muscle glucose metabolism and regeneration distinct from its neuronal functions.","method":"Dock3 conditional skeletal muscle-specific knockout mice, co-immunoprecipitation (DOCK3 and SORBS1), metabolic phenotyping, muscle histology, locomotor activity assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific metabolic and regenerative phenotypes, novel binding partner identified by co-IP, multiple orthogonal assays, peer-reviewed and preprint concordant","pmids":["37742307","36865261"],"is_preprint":false},{"year":2023,"finding":"ZBED6 transcription factor directly represses DOCK3 expression (ChIP-seq and RNA-seq), and in ZBED6-deficient septic pigs, increased DOCK3 expression activates the RAC1/PI3K/AKT pathway, protecting against sepsis-induced muscle wasting.","method":"ChIP-seq and RNA-seq in ZBED6-deficient pigs, Western blot (DOCK3, RAC1-GTP, pAKT), CLP sepsis pig model, ZBED6 overexpression in myotubes","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq establishes direct transcriptional regulation, functional pathway activation shown in vivo, single lab large animal model","pmids":["37551034"],"is_preprint":false},{"year":2023,"finding":"Low-molecular-weight compounds that stimulate the interaction between DOCK3 and Elmo1 promote neurite outgrowth in vitro and neuroprotection/axon regeneration in a mouse optic nerve injury model, confirming that the DOCK3-Elmo1 interaction is a functional node for Rac1 activation and axon elongation.","method":"High-throughput compound screen (462,169 compounds), DOCK3-Elmo1 interaction assay, neurite outgrowth assay, in vivo optic nerve crush model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional compound screen with mechanistic validation of DOCK3-Elmo1 interaction and in vivo regeneration, single lab","pmids":["37188749"],"is_preprint":false},{"year":2025,"finding":"HAUS7 (HAUS augmin-like complex subunit 7) is a direct binding partner of DOCK3. Neuronal HAUS7 is transported from the cell body to the growth cone under control of DOCK3. Phosphorylation of DOCK3 at Y562 by TrkB signaling causes dissociation of HAUS7, which is required for microtubule assembly and axon regeneration. Deletion of Haus7 significantly reduced microtubule formation and axon regeneration after optic nerve crush.","method":"Co-immunoprecipitation (DOCK3-HAUS7), phospho-specific mutagenesis (Y562), live imaging of HAUS7 transport, Haus7 conditional knockout mice with optic nerve crush, transcriptome analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, site-specific mutagenesis of phosphorylation site, KO mouse model with quantitative axon regeneration, multiple orthogonal methods","pmids":["40712007"],"is_preprint":false},{"year":2016,"finding":"Dock3 overexpression promotes internalization and degradation of NMDA receptors in the retina in vivo. This process is suggested to be mediated by inhibition of Fyn (a Src family tyrosine kinase), reducing excitotoxic damage and oxidative stress, thereby promoting RGC survival.","method":"In vivo Dock3 Tg mice with optic nerve crush or NMDA stimulation, Western blot for NMDA receptor subunit levels and Fyn activity, retinal ganglion cell survival counts","journal":"Histology and histopathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with receptor internalization readout and Fyn activity, single lab, review-style but with described experimental data","pmids":["27615513"],"is_preprint":false}],"current_model":"DOCK3 (also known as MOCA) is a neuronally-enriched, atypical guanine nucleotide exchange factor (GEF) that activates the small GTPase Rac1 through its DHR-2 catalytic domain; it promotes axonal outgrowth and cytoskeletal reorganization by (1) recruiting the WAVE1 complex to the plasma membrane via its DHR-1 domain downstream of BDNF-TrkB signaling, followed by phosphorylation-dependent dissociation; (2) binding GSK-3β to increase active CRMP-2 for microtubule assembly; (3) forming a ternary complex with Elmo and RhoG to amplify Rac1 activation; (4) binding and promoting internalization/degradation of NMDA receptor subunits NR2B and NR2D to confer neuroprotection; (5) acting as a negative regulator of Wnt/β-catenin signaling by sequestering β-catenin at the membrane; and (6) in skeletal muscle, interacting with SORBS1 through its C-terminal domain to regulate glucose metabolism and myofiber regeneration, and being transcriptionally repressed by ZBED6 to modulate the RAC1/PI3K/AKT pathway."},"narrative":{"mechanistic_narrative":"DOCK3 (MOCA) is a neuronally-enriched atypical guanine nucleotide exchange factor that drives Rac1 activation to control cytoskeletal remodeling, axon outgrowth, and neuroprotection [PMID:14718541, PMID:20368433]. It binds Rac1 directly and enhances its GTPase loading through catalytic residues in the DHR-2 domain, concentrating at lamellipodial leading edges and growth cones and coupling Rac1 activation to JNK signaling [PMID:14718541, PMID:30976111]. Downstream of BDNF-TrkB signaling, DOCK3 is recruited to the plasma membrane where it engages the WAVE complex via its DHR-1 domain and, after phosphorylation, dissociates to permit Rac1-driven axonal outgrowth [PMID:20368433]; it forms a ternary complex with Elmo and activated RhoG that amplifies Rac1 activation, a node functionally validated by small molecules that stabilize the DOCK3-Elmo1 interaction and promote axon regeneration [PMID:22734669, PMID:37188749]. In parallel, DOCK3 promotes microtubule assembly by inactivating GSK-3β to increase active CRMP-2, and by TrkB-dependent phosphorylation at Y562 that releases HAUS7 for transport to the growth cone [PMID:22219288, PMID:40712007]. DOCK3 also confers neuroprotection by binding the C-terminal tails of NMDA receptor subunits NR2B and NR2D to reduce their surface expression and promote internalization, limiting excitotoxic retinal ganglion cell death [PMID:23852370, PMID:23641686, PMID:27615513]. Independently, DOCK3 acts as a negative regulator of Wnt/β-catenin signaling by sequestering β-catenin at the membrane to suppress nuclear translocation and target-gene transcription [PMID:18716063]. In skeletal muscle, DOCK3 interacts with SORBS1 through its C-terminal domain and is a dosage-sensitive regulator of glucose metabolism, myofiber regeneration, and myogenic differentiation, acting through RAC1/PI3K/AKT and PTEN/AKT signaling [PMID:24789910, PMID:32766788, PMID:37742307, PMID:36865261]. Loss-of-function DOCK3 missense variants in the DHR-2 domain reduce Rac1 GEF activity and underlie a neurodevelopmental phenotype [PMID:30976111].","teleology":[{"year":2004,"claim":"Established DOCK3 as a Rac1-binding activator, defining its core molecular activity and linking it to actin-based morphology in neurons.","evidence":"Co-IP, Rac1 GTPase pull-down, farnesylated membrane-targeted construct, and immunofluorescence in cortical neurons","pmids":["14718541"],"confidence":"High","gaps":["DHR-2 catalytic mechanism not yet resolved at this stage","physiological upstream signal not defined"]},{"year":2008,"claim":"Identified a non-cytoskeletal role: DOCK3 negatively regulates Wnt/β-catenin signaling by retaining β-catenin at the membrane.","evidence":"cDNA library screen, co-IP, Wnt luciferase reporter, fractionation, and epistasis in human cells","pmids":["18716063"],"confidence":"High","gaps":["domain mediating β-catenin binding not mapped","relationship to GEF activity unclear"]},{"year":2010,"claim":"Defined the BDNF-TrkB → DOCK3/WAVE membrane recruitment cascade and pinpointed DHR-2 catalytic residues, mechanistically grounding axon outgrowth.","evidence":"Domain mutagenesis, reciprocal co-IP, membrane fractionation, and in vivo optic nerve regeneration in Dock3 Tg mice","pmids":["20368433"],"confidence":"High","gaps":["identity of the kinase phosphorylating DOCK3 not established here","stoichiometry of the DOCK3/WAVE complex unresolved"]},{"year":2012,"claim":"Extended DOCK3 function to microtubule control via GSK-3β inactivation/CRMP-2 and to Rac1 amplification through an Elmo/RhoG ternary complex.","evidence":"Co-IP, phosphorylation Western blots in hippocampal neurons, Rac1 pull-down, phospho-site mutagenesis, and neurite outgrowth in PC12 cells","pmids":["22219288","22734669"],"confidence":"High","gaps":["how membrane recruitment, GSK-3β binding, and Elmo binding are temporally coordinated is unclear","direct kinase responsible for DOCK3 phosphorylation not identified"]},{"year":2012,"claim":"Placed DOCK3 as an integrator of Alzheimer-linked APP and presenilin death signals between Rac1/Cdc42 and ASK1.","evidence":"Cell death assays with AD mutant constructs and epistasis via MOCA overexpression/knockdown in neuronal cells","pmids":["22115042"],"confidence":"Medium","gaps":["mechanistic placement inferred from epistasis, not direct biochemistry","physiological relevance in vivo not tested","single lab"]},{"year":2013,"claim":"Defined a neuroprotective mechanism: DOCK3 binds NR2B and NR2D C-termini to lower NMDA receptor surface levels and limit excitotoxic RGC death.","evidence":"Co-IP of DOCK3 with NR2B/NR2D C-termini, surface expression assays, and quantitative RGC counts in Dock3 Tg, GLAST-KO, and NR2D-KO mice","pmids":["23852370","23641686"],"confidence":"High","gaps":["mechanism of receptor internalization not resolved at this stage","whether GEF activity is required for receptor regulation untested"]},{"year":2014,"claim":"Revealed DOCK3 as a miR-486 target in skeletal muscle that modulates PTEN/AKT signaling and apoptosis, opening a non-neuronal role.","evidence":"3'UTR luciferase validation, DOCK3 overexpression in human myotubes, PTEN/pAKT Western blots, and miR-486 transgenic mice on DMD background","pmids":["24789910"],"confidence":"High","gaps":["direct biochemical link between DOCK3 and PTEN/AKT not established","GEF dependence of the muscle phenotype unclear"]},{"year":2014,"claim":"Showed DOCK3 protects myelin via increased ERK activation in a demyelination model, extending its protective role to oligodendrocytes.","evidence":"Cuprizone demyelination in Dock3 Tg mice, immunohistochemistry, electroretinogram, and pErk Western blot","pmids":["25165881"],"confidence":"Medium","gaps":["how DOCK3 couples to ERK not defined","single lab, overexpression-based"]},{"year":2015,"claim":"Implicated DOCK3 in pathological Rac1 activity in both cancer cell invasion and epileptogenesis.","evidence":"miR-512-3p/siRNA knockdown with active RAC1 pull-down and migration/invasion in NSCLC lines; Dock3 shRNA with Rac1-GTP and seizure scoring in mouse kindling models","pmids":["25687035","26319681"],"confidence":"Medium","gaps":["direct partners in these contexts not mapped","single lab per context"]},{"year":2016,"claim":"Linked DOCK3-mediated β-catenin suppression to WAVE2 expression and lamellipodial/tumor cell motility, and proposed Fyn inhibition as the route to NMDA receptor internalization.","evidence":"Co-IP, in vitro kinase assays, knockdown with migration readouts; in vivo Dock3 Tg with NMDA receptor and Fyn activity measurements","pmids":["26716413","27615513"],"confidence":"Medium","gaps":["Fyn-mediated internalization mechanism is suggested, not directly proven","single lab studies"]},{"year":2019,"claim":"Connected DOCK3 to human disease by showing DHR-2 missense variants reduce Rac1 GEF activity, establishing loss-of-function as the basis of a neurodevelopmental phenotype.","evidence":"Patient-variant mutagenesis with active Rac1 pull-down and structural modeling","pmids":["30976111"],"confidence":"Medium","gaps":["limited patient numbers","in vivo consequence of variants not modeled","single lab"]},{"year":2020,"claim":"Defined DOCK3 as a dosage-sensitive regulator of muscle, where haploinsufficiency benefits but complete loss worsens dystrophic muscle and impairs myogenic differentiation.","evidence":"Dock3 KO crossed with mdx mice, muscle function tests, myoblast differentiation, and RNA-seq","pmids":["32766788"],"confidence":"Medium","gaps":["molecular basis of the dosage sensitivity unresolved","single lab"]},{"year":2023,"claim":"Established a distinct muscle-metabolic role through SORBS1 binding and identified ZBED6 as a direct transcriptional repressor acting via RAC1/PI3K/AKT.","evidence":"Muscle-specific Dock3 conditional KO with metabolic phenotyping and DOCK3-SORBS1 co-IP; ChIP-seq/RNA-seq and CLP sepsis model in ZBED6-deficient pigs","pmids":["37742307","36865261","37551034"],"confidence":"High","gaps":["how SORBS1 binding feeds into glucose metabolism mechanistically is unresolved","whether GEF activity is required for the metabolic role untested"]},{"year":2023,"claim":"Validated the DOCK3-Elmo1 interaction as a druggable functional node for Rac1-driven axon regeneration.","evidence":"High-throughput compound screen, DOCK3-Elmo1 interaction assay, neurite outgrowth, and in vivo optic nerve crush","pmids":["37188749"],"confidence":"Medium","gaps":["binding site of compounds not defined","single lab"]},{"year":2025,"claim":"Identified HAUS7 as a DOCK3-controlled cargo whose TrkB/Y562-phosphorylation-dependent release from DOCK3 enables microtubule assembly and axon regeneration.","evidence":"Reciprocal co-IP, Y562 phospho-site mutagenesis, live imaging of HAUS7 transport, and Haus7 conditional KO with optic nerve crush","pmids":["40712007"],"confidence":"High","gaps":["kinase directly phosphorylating Y562 not identified","relationship between HAUS7 transport and the WAVE/Elmo modules unresolved"]},{"year":null,"claim":"How DOCK3's multiple binding modules (WAVE, Elmo/RhoG, GSK-3β, HAUS7, NMDA receptors, β-catenin, SORBS1) are spatially and temporally coordinated downstream of a single phosphorylation switch remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no integrated structural or temporal model of DOCK3 complex switching","identity of the DOCK3 kinase(s) not established","whether neuronal and muscle functions share a common biochemical mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5,19]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[8,14,15]}],"complexes":[],"partners":["RAC1","WAVE1","ELMO1","RHOG","GSK3B","GRIN2B","CTNNB1","SORBS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZD9","full_name":"Dedicator of cytokinesis protein 3","aliases":["Modifier of cell adhesion","PS binding protein","PBP","Presenilin-binding protein"],"length_aa":2030,"mass_kda":233.1,"function":"Potential guanine nucleotide exchange factor (GEF). GEF proteins activate some small GTPases by exchanging bound GDP for free GTP. Its interaction with presenilin proteins as well as its ability to stimulate Tau/MAPT phosphorylation suggest that it may be involved in Alzheimer disease. Ectopic expression in nerve cells decreases the secretion of amyloid-beta APBA1 protein and lowers the rate of cell-substratum adhesion, suggesting that it may affect the function of some small GTPase involved in the regulation of actin cytoskeleton or cell adhesion receptors (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8IZD9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOCK3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DOCK3","total_profiled":1310},"omim":[{"mim_id":"618292","title":"NEURODEVELOPMENTAL DISORDER WITH IMPAIRED INTELLECTUAL DEVELOPMENT, HYPOTONIA, AND ATAXIA; 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Farnesylated MOCA localized to the plasma membrane showed enhanced Rac1 and JNK activation. Endogenous MOCA concentrates at lamellipodia leading edges and growth cones co-localized with actin filaments.\",\n      \"method\": \"Co-immunoprecipitation, GTPase activity assay (Rac1 pull-down), overexpression of farnesylated vs. wild-type MOCA, immunofluorescence in cortical neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, GTPase activity assay, multiple cell morphology readouts, replicated with farnesylated construct and primary neurons\",\n      \"pmids\": [\"14718541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DOCK3 directly associates with WAVE proteins through its DHR-1 domain. BDNF-TrkB signaling recruits the DOCK3/WAVE1 complex to the plasma membrane, whereupon DOCK3 activates Rac1 and dissociates from the WAVE complex in a phosphorylation-dependent manner, driving axonal outgrowth. Key conserved amino acids in the DHR-2 domain are critical for catalytic GEF activity of DOCK3.\",\n      \"method\": \"Co-immunoprecipitation, DHR-1/DHR-2 domain mutagenesis, membrane fractionation, in vivo optic nerve regeneration in Dock3 transgenic mice, neurite outgrowth assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mutagenesis identifying catalytic residues, reciprocal co-IP, in vitro and in vivo assays in multiple systems\",\n      \"pmids\": [\"20368433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK3 binds to and inactivates GSK-3β at the plasma membrane, increasing the non-phosphorylated active form of CRMP-2, which promotes microtubule assembly and axon branching. BDNF induced GSK-3β phosphorylation and CRMP-2 dephosphorylation in hippocampal neurons, and elevated GSK-3β phosphorylation was detected in regenerating axons of Dock3 transgenic mice after optic nerve injury.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays (Western blot), primary hippocampal neuron culture, in vivo optic nerve crush in Dock3 Tg mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus functional phosphorylation assays in vitro and in vivo in transgenic mice, two orthogonal methods\",\n      \"pmids\": [\"22219288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK3 forms a ternary complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling to induce neurite outgrowth via Rac1 activation in PC12 cells. Phosphorylation of DOCK3 and its interaction with Elmo are both required for efficient Rac1 activation; membrane recruitment of DOCK3 is also necessary.\",\n      \"method\": \"Co-immunoprecipitation, Rac1 pull-down (active GTP-bound Rac1 assay), neurite outgrowth assay in PC12 cells, site-directed mutagenesis of phosphorylation sites\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, GTPase activity assay, mutagenesis, functional neurite outgrowth readout, single lab\",\n      \"pmids\": [\"22734669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOCK3 directly binds to the intracellular C-terminus domain of NR2B (GluN2B), an NMDA receptor subunit. Overexpression of DOCK3 in transgenic mice decreased NR2B expression in the retina and ameliorated NMDA-induced retinal degeneration. DOCK3 overexpression also suppressed phosphorylation of NR2B in GLAST-KO mice, reducing excitotoxic and oxidative stress-related RGC death.\",\n      \"method\": \"Co-immunoprecipitation (DOCK3 and NR2B C-terminus), Western blot, in vivo retinal degeneration assay in Dock3 Tg and GLAST KO mice, NMDA injection model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding shown by co-IP, functional validation in multiple transgenic mouse models with quantitative retinal degeneration readouts\",\n      \"pmids\": [\"23852370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOCK3 binds to the NR2D C-terminal domain and reduces surface expression of NR2D, thereby protecting retinal ganglion cells from excitotoxicity. NR2D deficiency also attenuates RGC loss in GLAST-deficient mice.\",\n      \"method\": \"Co-immunoprecipitation (DOCK3 and NR2D C-terminus), surface expression assay, genetic mouse models (NR2D KO × GLAST KO), RGC counting\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by co-IP, surface expression assay, multiple genetic mouse models with quantitative RGC loss phenotype\",\n      \"pmids\": [\"23641686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MOCA/DOCK3 functions as a negative regulator of Wnt/β-catenin signaling. MOCA forms a complex with β-catenin and inhibits transcription of Wnt target genes, reduces nuclear β-catenin levels, increases membrane-bound β-catenin levels, and enhances cell-cell adhesion. Epistasis experiments placed MOCA action at the level of reducing nuclear β-catenin.\",\n      \"method\": \"Functional cDNA library screen in human cells, co-immunoprecipitation (MOCA and β-catenin), Wnt target gene luciferase reporter assay, subcellular fractionation, cell-cell adhesion assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, luciferase reporter, fractionation, and epistasis all in same study; multiple orthogonal methods\",\n      \"pmids\": [\"18716063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MOCA/DOCK3 is a downstream integrator of neuronal death signals from both familial AD-linked APP mutants and presenilin (PS1/PS2) mutants, in a γ-secretase-independent manner. MOCA links PS-mediated death signals with APP-mediated death signals at a point between Rac1/Cdc42 and ASK1 (apoptosis signal-regulating kinase 1).\",\n      \"method\": \"Cell death assays with AD mutant constructs (APP, PS1, PS2), epistasis analysis using MOCA overexpression/knockdown, genetic interaction experiments in neuronal cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and cell-based functional assays, single lab, mechanistic placement between Rac1/Cdc42 and ASK1 inferred from knockdown/overexpression\",\n      \"pmids\": [\"22115042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOCK3 is a direct target of miR-486 in skeletal muscle. Overexpression of DOCK3 in human myotubes modulates PTEN/AKT signaling (increases PTEN and reduces phosphorylated AKT) and induces apoptosis. In dystrophic mice, miR-486 overexpression decreases DOCK3 levels, reduces PTEN expression, and increases phospho-AKT.\",\n      \"method\": \"miR-486 target validation (3'UTR luciferase), DOCK3 overexpression in human myotubes, Western blot for PTEN/pAKT, in vivo miR-486 transgenic mice on DMD background\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — target validation, functional overexpression assays, in vivo transgenic model, multiple signaling readouts, independently confirmed in multiple systems\",\n      \"pmids\": [\"24789910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DOCK3, as a RAC1-GEF, is a target of miR-512-3p in NSCLC cells. Knockdown of DOCK3 inhibited cell adhesion, migration, and invasion, and decreased active RAC1 levels, demonstrating that DOCK3 promotes RAC1 activity and metastatic behaviors in lung cancer cells.\",\n      \"method\": \"miR-512-3p overexpression, DOCK3 siRNA knockdown, active RAC1 pull-down assay, cell migration/invasion assays in A549 and H1299 cell lines\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active GTPase pull-down, functional migration/invasion assays, knockdown, single lab two orthogonal methods\",\n      \"pmids\": [\"25687035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DOCK3 acts as a negative regulator of WAVE2 expression by blocking β-catenin nuclear translocation; phospho-Annexin A2 (pY23) promotes DOCK3 expression, and DOCK3 inhibits lamellipodium dynamics and tumor cell movement via suppression of β-catenin/WAVE2 signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (Src/CD147/Annexin A2), DOCK3 knockdown, Western blot, cell migration assay, β-catenin subcellular localization\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, knockdown with functional migration readout, single lab\",\n      \"pmids\": [\"26716413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOCK3 is expressed in oligodendrocytes, and Dock3 overexpression protects myelin in the corpus callosum and optic nerves in a cuprizone-induced demyelination model. In Dock3 Tg mice, Erk activation is increased, suggesting ERK signaling as part of the Dock3-mediated protective mechanism.\",\n      \"method\": \"Immunohistochemistry for oligodendrocyte markers, cuprizone demyelination model in Dock3 Tg mice, multifocal electroretinogram, Western blot (pErk)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model, functional visual readout, ERK phosphorylation assay, single lab\",\n      \"pmids\": [\"25165881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dock3 expression increases in epileptic brain tissue and models, and Dock3 shRNA knockdown reduces Rac1-GTP levels, decreases severity of status epilepticus, reduces spontaneous recurrent seizures, and increases latency in a kindling model, placing Dock3 upstream of Rac1 in epileptogenesis.\",\n      \"method\": \"shRNA knockdown of Dock3 in lithium-pilocarpine and pentylenetetrazole kindling mouse models, active Rac1 pull-down, behavioral seizure scoring\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with behavioral readout plus active Rac1 measurement, single lab\",\n      \"pmids\": [\"26319681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DOCK3 missense variants in or adjacent to the DHR-2 domain significantly reduce Rac1 GEF activity compared to wild-type DOCK3, confirming that the DHR-2 domain is critical for Rac1 activation and that loss-of-function of this activity underlies the neurodevelopmental phenotype.\",\n      \"method\": \"Site-directed mutagenesis of patient missense variants, Rac1 pull-down (active GTP-bound Rac1) assay in transfected cells, protein structural modeling\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro mutagenesis with GTPase activity assay, single lab, limited patient numbers\",\n      \"pmids\": [\"30976111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DOCK3 is a dosage-sensitive modulator of skeletal muscle function. Haploinsufficiency of Dock3 in DMD mice improved dystrophic muscle pathologies, but complete knockout worsened muscle function. Dock3 KO myoblasts are defective in myogenic differentiation, with transcriptomic analyses revealing decreased myogenic factors.\",\n      \"method\": \"Dock3 global knockout mice crossed with mdx dystrophic mice, muscle function tests, myoblast differentiation assays, RNA-seq transcriptomics\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in two disease-relevant models, functional muscle assays, transcriptomics, single lab\",\n      \"pmids\": [\"32766788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DOCK3 directly interacts with SORBS1 through its C-terminal domain in skeletal muscle. Conditional muscle-specific Dock3 knockout (mKO) mice display hyperglycemia, increased fat mass, impaired myofiber regeneration, and metabolic dysfunction, establishing a role for DOCK3 in skeletal muscle glucose metabolism and regeneration distinct from its neuronal functions.\",\n      \"method\": \"Dock3 conditional skeletal muscle-specific knockout mice, co-immunoprecipitation (DOCK3 and SORBS1), metabolic phenotyping, muscle histology, locomotor activity assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific metabolic and regenerative phenotypes, novel binding partner identified by co-IP, multiple orthogonal assays, peer-reviewed and preprint concordant\",\n      \"pmids\": [\"37742307\", \"36865261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZBED6 transcription factor directly represses DOCK3 expression (ChIP-seq and RNA-seq), and in ZBED6-deficient septic pigs, increased DOCK3 expression activates the RAC1/PI3K/AKT pathway, protecting against sepsis-induced muscle wasting.\",\n      \"method\": \"ChIP-seq and RNA-seq in ZBED6-deficient pigs, Western blot (DOCK3, RAC1-GTP, pAKT), CLP sepsis pig model, ZBED6 overexpression in myotubes\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq establishes direct transcriptional regulation, functional pathway activation shown in vivo, single lab large animal model\",\n      \"pmids\": [\"37551034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Low-molecular-weight compounds that stimulate the interaction between DOCK3 and Elmo1 promote neurite outgrowth in vitro and neuroprotection/axon regeneration in a mouse optic nerve injury model, confirming that the DOCK3-Elmo1 interaction is a functional node for Rac1 activation and axon elongation.\",\n      \"method\": \"High-throughput compound screen (462,169 compounds), DOCK3-Elmo1 interaction assay, neurite outgrowth assay, in vivo optic nerve crush model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional compound screen with mechanistic validation of DOCK3-Elmo1 interaction and in vivo regeneration, single lab\",\n      \"pmids\": [\"37188749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HAUS7 (HAUS augmin-like complex subunit 7) is a direct binding partner of DOCK3. Neuronal HAUS7 is transported from the cell body to the growth cone under control of DOCK3. Phosphorylation of DOCK3 at Y562 by TrkB signaling causes dissociation of HAUS7, which is required for microtubule assembly and axon regeneration. Deletion of Haus7 significantly reduced microtubule formation and axon regeneration after optic nerve crush.\",\n      \"method\": \"Co-immunoprecipitation (DOCK3-HAUS7), phospho-specific mutagenesis (Y562), live imaging of HAUS7 transport, Haus7 conditional knockout mice with optic nerve crush, transcriptome analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, site-specific mutagenesis of phosphorylation site, KO mouse model with quantitative axon regeneration, multiple orthogonal methods\",\n      \"pmids\": [\"40712007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dock3 overexpression promotes internalization and degradation of NMDA receptors in the retina in vivo. This process is suggested to be mediated by inhibition of Fyn (a Src family tyrosine kinase), reducing excitotoxic damage and oxidative stress, thereby promoting RGC survival.\",\n      \"method\": \"In vivo Dock3 Tg mice with optic nerve crush or NMDA stimulation, Western blot for NMDA receptor subunit levels and Fyn activity, retinal ganglion cell survival counts\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with receptor internalization readout and Fyn activity, single lab, review-style but with described experimental data\",\n      \"pmids\": [\"27615513\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOCK3 (also known as MOCA) is a neuronally-enriched, atypical guanine nucleotide exchange factor (GEF) that activates the small GTPase Rac1 through its DHR-2 catalytic domain; it promotes axonal outgrowth and cytoskeletal reorganization by (1) recruiting the WAVE1 complex to the plasma membrane via its DHR-1 domain downstream of BDNF-TrkB signaling, followed by phosphorylation-dependent dissociation; (2) binding GSK-3β to increase active CRMP-2 for microtubule assembly; (3) forming a ternary complex with Elmo and RhoG to amplify Rac1 activation; (4) binding and promoting internalization/degradation of NMDA receptor subunits NR2B and NR2D to confer neuroprotection; (5) acting as a negative regulator of Wnt/β-catenin signaling by sequestering β-catenin at the membrane; and (6) in skeletal muscle, interacting with SORBS1 through its C-terminal domain to regulate glucose metabolism and myofiber regeneration, and being transcriptionally repressed by ZBED6 to modulate the RAC1/PI3K/AKT pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOCK3 (MOCA) is a neuronally-enriched atypical guanine nucleotide exchange factor that drives Rac1 activation to control cytoskeletal remodeling, axon outgrowth, and neuroprotection [#0, #1]. It binds Rac1 directly and enhances its GTPase loading through catalytic residues in the DHR-2 domain, concentrating at lamellipodial leading edges and growth cones and coupling Rac1 activation to JNK signaling [#0, #13]. Downstream of BDNF-TrkB signaling, DOCK3 is recruited to the plasma membrane where it engages the WAVE complex via its DHR-1 domain and, after phosphorylation, dissociates to permit Rac1-driven axonal outgrowth [#1]; it forms a ternary complex with Elmo and activated RhoG that amplifies Rac1 activation, a node functionally validated by small molecules that stabilize the DOCK3-Elmo1 interaction and promote axon regeneration [#3, #17]. In parallel, DOCK3 promotes microtubule assembly by inactivating GSK-3\\u03b2 to increase active CRMP-2, and by TrkB-dependent phosphorylation at Y562 that releases HAUS7 for transport to the growth cone [#2, #18]. DOCK3 also confers neuroprotection by binding the C-terminal tails of NMDA receptor subunits NR2B and NR2D to reduce their surface expression and promote internalization, limiting excitotoxic retinal ganglion cell death [#4, #5, #19]. Independently, DOCK3 acts as a negative regulator of Wnt/\\u03b2-catenin signaling by sequestering \\u03b2-catenin at the membrane to suppress nuclear translocation and target-gene transcription [#6]. In skeletal muscle, DOCK3 interacts with SORBS1 through its C-terminal domain and is a dosage-sensitive regulator of glucose metabolism, myofiber regeneration, and myogenic differentiation, acting through RAC1/PI3K/AKT and PTEN/AKT signaling [#8, #14, #15]. Loss-of-function DOCK3 missense variants in the DHR-2 domain reduce Rac1 GEF activity and underlie a neurodevelopmental phenotype [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established DOCK3 as a Rac1-binding activator, defining its core molecular activity and linking it to actin-based morphology in neurons.\",\n      \"evidence\": \"Co-IP, Rac1 GTPase pull-down, farnesylated membrane-targeted construct, and immunofluorescence in cortical neurons\",\n      \"pmids\": [\"14718541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DHR-2 catalytic mechanism not yet resolved at this stage\", \"physiological upstream signal not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a non-cytoskeletal role: DOCK3 negatively regulates Wnt/\\u03b2-catenin signaling by retaining \\u03b2-catenin at the membrane.\",\n      \"evidence\": \"cDNA library screen, co-IP, Wnt luciferase reporter, fractionation, and epistasis in human cells\",\n      \"pmids\": [\"18716063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"domain mediating \\u03b2-catenin binding not mapped\", \"relationship to GEF activity unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the BDNF-TrkB \\u2192 DOCK3/WAVE membrane recruitment cascade and pinpointed DHR-2 catalytic residues, mechanistically grounding axon outgrowth.\",\n      \"evidence\": \"Domain mutagenesis, reciprocal co-IP, membrane fractionation, and in vivo optic nerve regeneration in Dock3 Tg mice\",\n      \"pmids\": [\"20368433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"identity of the kinase phosphorylating DOCK3 not established here\", \"stoichiometry of the DOCK3/WAVE complex unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended DOCK3 function to microtubule control via GSK-3\\u03b2 inactivation/CRMP-2 and to Rac1 amplification through an Elmo/RhoG ternary complex.\",\n      \"evidence\": \"Co-IP, phosphorylation Western blots in hippocampal neurons, Rac1 pull-down, phospho-site mutagenesis, and neurite outgrowth in PC12 cells\",\n      \"pmids\": [\"22219288\", \"22734669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how membrane recruitment, GSK-3\\u03b2 binding, and Elmo binding are temporally coordinated is unclear\", \"direct kinase responsible for DOCK3 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed DOCK3 as an integrator of Alzheimer-linked APP and presenilin death signals between Rac1/Cdc42 and ASK1.\",\n      \"evidence\": \"Cell death assays with AD mutant constructs and epistasis via MOCA overexpression/knockdown in neuronal cells\",\n      \"pmids\": [\"22115042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic placement inferred from epistasis, not direct biochemistry\", \"physiological relevance in vivo not tested\", \"single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a neuroprotective mechanism: DOCK3 binds NR2B and NR2D C-termini to lower NMDA receptor surface levels and limit excitotoxic RGC death.\",\n      \"evidence\": \"Co-IP of DOCK3 with NR2B/NR2D C-termini, surface expression assays, and quantitative RGC counts in Dock3 Tg, GLAST-KO, and NR2D-KO mice\",\n      \"pmids\": [\"23852370\", \"23641686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of receptor internalization not resolved at this stage\", \"whether GEF activity is required for receptor regulation untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed DOCK3 as a miR-486 target in skeletal muscle that modulates PTEN/AKT signaling and apoptosis, opening a non-neuronal role.\",\n      \"evidence\": \"3'UTR luciferase validation, DOCK3 overexpression in human myotubes, PTEN/pAKT Western blots, and miR-486 transgenic mice on DMD background\",\n      \"pmids\": [\"24789910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct biochemical link between DOCK3 and PTEN/AKT not established\", \"GEF dependence of the muscle phenotype unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed DOCK3 protects myelin via increased ERK activation in a demyelination model, extending its protective role to oligodendrocytes.\",\n      \"evidence\": \"Cuprizone demyelination in Dock3 Tg mice, immunohistochemistry, electroretinogram, and pErk Western blot\",\n      \"pmids\": [\"25165881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how DOCK3 couples to ERK not defined\", \"single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated DOCK3 in pathological Rac1 activity in both cancer cell invasion and epileptogenesis.\",\n      \"evidence\": \"miR-512-3p/siRNA knockdown with active RAC1 pull-down and migration/invasion in NSCLC lines; Dock3 shRNA with Rac1-GTP and seizure scoring in mouse kindling models\",\n      \"pmids\": [\"25687035\", \"26319681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct partners in these contexts not mapped\", \"single lab per context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked DOCK3-mediated \\u03b2-catenin suppression to WAVE2 expression and lamellipodial/tumor cell motility, and proposed Fyn inhibition as the route to NMDA receptor internalization.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, knockdown with migration readouts; in vivo Dock3 Tg with NMDA receptor and Fyn activity measurements\",\n      \"pmids\": [\"26716413\", \"27615513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fyn-mediated internalization mechanism is suggested, not directly proven\", \"single lab studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected DOCK3 to human disease by showing DHR-2 missense variants reduce Rac1 GEF activity, establishing loss-of-function as the basis of a neurodevelopmental phenotype.\",\n      \"evidence\": \"Patient-variant mutagenesis with active Rac1 pull-down and structural modeling\",\n      \"pmids\": [\"30976111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"limited patient numbers\", \"in vivo consequence of variants not modeled\", \"single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined DOCK3 as a dosage-sensitive regulator of muscle, where haploinsufficiency benefits but complete loss worsens dystrophic muscle and impairs myogenic differentiation.\",\n      \"evidence\": \"Dock3 KO crossed with mdx mice, muscle function tests, myoblast differentiation, and RNA-seq\",\n      \"pmids\": [\"32766788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular basis of the dosage sensitivity unresolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a distinct muscle-metabolic role through SORBS1 binding and identified ZBED6 as a direct transcriptional repressor acting via RAC1/PI3K/AKT.\",\n      \"evidence\": \"Muscle-specific Dock3 conditional KO with metabolic phenotyping and DOCK3-SORBS1 co-IP; ChIP-seq/RNA-seq and CLP sepsis model in ZBED6-deficient pigs\",\n      \"pmids\": [\"37742307\", \"36865261\", \"37551034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how SORBS1 binding feeds into glucose metabolism mechanistically is unresolved\", \"whether GEF activity is required for the metabolic role untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated the DOCK3-Elmo1 interaction as a druggable functional node for Rac1-driven axon regeneration.\",\n      \"evidence\": \"High-throughput compound screen, DOCK3-Elmo1 interaction assay, neurite outgrowth, and in vivo optic nerve crush\",\n      \"pmids\": [\"37188749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"binding site of compounds not defined\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified HAUS7 as a DOCK3-controlled cargo whose TrkB/Y562-phosphorylation-dependent release from DOCK3 enables microtubule assembly and axon regeneration.\",\n      \"evidence\": \"Reciprocal co-IP, Y562 phospho-site mutagenesis, live imaging of HAUS7 transport, and Haus7 conditional KO with optic nerve crush\",\n      \"pmids\": [\"40712007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"kinase directly phosphorylating Y562 not identified\", \"relationship between HAUS7 transport and the WAVE/Elmo modules unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DOCK3's multiple binding modules (WAVE, Elmo/RhoG, GSK-3\\u03b2, HAUS7, NMDA receptors, \\u03b2-catenin, SORBS1) are spatially and temporally coordinated downstream of a single phosphorylation switch remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no integrated structural or temporal model of DOCK3 complex switching\", \"identity of the DOCK3 kinase(s) not established\", \"whether neuronal and muscle functions share a common biochemical mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5, 19]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [8, 14, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAC1\", \"WAVE1\", \"ELMO1\", \"RHOG\", \"GSK3B\", \"GRIN2B\", \"CTNNB1\", \"SORBS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}