{"gene":"DOCK7","run_date":"2026-06-14T07:33:11","timeline":{"discoveries":[{"year":2006,"finding":"DOCK7 is a Rac GTPase activator that is asymmetrically distributed in unpolarized hippocampal neurons and selectively expressed in the nascent axon; DOCK7 knockdown prevents axon formation while overexpression induces multiple axons; DOCK7 and Rac activation lead to phosphorylation and inactivation of the microtubule destabilizing protein stathmin/Op18 in the nascent axon, establishing a DOCK7→Rac→stathmin/Op18 pathway for axon development.","method":"shRNA knockdown, overexpression, immunofluorescence localization, phospho-stathmin assays in hippocampal neurons","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, localization, phosphorylation assay) in a single focused study, replicated across conditions","pmids":["16982419"],"is_preprint":false},{"year":2008,"finding":"The NRG1 receptor ErbB2 directly binds and phosphorylates DOCK7 at Tyr-1118, activating DOCK7 GEF activity toward Rac1 and Cdc42, which in turn activates JNK to promote Schwann cell migration; a Y1118F mutant of DOCK7 fails to transduce NRG1 signals.","method":"Co-immunoprecipitation, site-directed mutagenesis (Y1118F), Rho GTPase pull-down activity assays, siRNA knockdown, Schwann cell migration assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct phosphorylation demonstrated with mutagenesis, reciprocal Co-IP, GTPase activity assays, and functional migration rescue","pmids":["18426980"],"is_preprint":false},{"year":2011,"finding":"DOCK7 negatively regulates Schwann cell differentiation and onset of myelination: DOCK7 knockdown shortens Rac/Cdc42/JNK activation (negative regulator of myelination) and accelerates Rho/ROCK activation (positive regulator of myelination), resulting in enhanced myelin thickness in Dock7 shRNA transgenic mice.","method":"siRNA knockdown in primary Schwann cells, shRNA transgenic mouse generation, Rho GTPase activity assays, myelin thickness measurement","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo genetic KD with defined signaling and morphological readouts, consistent results across both systems","pmids":["21880919"],"is_preprint":false},{"year":2012,"finding":"DOCK7 interacts with the centrosome-associated protein TACC3 and antagonizes its microtubule growth-promoting function to control apically directed interkinetic nuclear migration of radial glial progenitor cells (RGCs), thereby regulating the switch from proliferative to differentiative divisions during cortical neurogenesis.","method":"In utero electroporation-based DOCK7 silencing/overexpression, co-immunoprecipitation of DOCK7 and TACC3, interkinetic nuclear migration assays, neuronal differentiation quantification","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying TACC3 as binding partner, combined with in vivo gain/loss-of-function and defined cellular phenotype (INM, progenitor vs. differentiation fate)","pmids":["22842144"],"is_preprint":false},{"year":2012,"finding":"DOCK7 binds to the cytoplasmic domain of RAGE (receptor for advanced glycation end-products) via co-immunoprecipitation/MS, and transduces RAGE signaling to Cdc42, resulting in formation of dendritic pseudopodia and promoting cancer cell migration.","method":"Immunoprecipitation–LC-MS/MS screen of RAGE cytoplasmic domain interactors, co-immunoprecipitation validation, Cdc42 activity assay, DOCK7 knockdown with cell migration and morphology readouts","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with MS identification, GTPase activity assay, and functional KD phenotype; single lab study","pmids":["23254359"],"is_preprint":false},{"year":2013,"finding":"The DHR2 (GEF) domain of DOCK7 is a potent guanine nucleotide exchange factor for prenylated Cdc42 and Rac1 on membrane liposomes, but not for non-prenylated GTPases in solution; membrane localization of Cdc42/Rac1 is required for DOCK7-mediated activation. An N-terminal site within DHR2 (distinct from the catalytic active site) preferentially binds GTP-loaded Cdc42/Rac1 and recruits DHR2 to the membrane, creating positive cooperativity that accelerates nucleotide exchange.","method":"Liposome reconstitution assay, in vitro GEF activity assay with prenylated vs. non-prenylated GTPases, site-directed mutagenesis to identify GTPase-selectivity residues","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with liposomes, mutagenesis of catalytic and allosteric sites, multiple orthogonal enzymatic assays","pmids":["23718289"],"is_preprint":false},{"year":2014,"finding":"DOCK7 functions as a cytoplasmic activator of the ErbB4 receptor tyrosine kinase in chandelier cells (ChCs); DOCK7 modulates ErbB4 activity and is required for chandelier cell cartridge and bouton development in vivo.","method":"In utero electroporation-based genetic labeling and manipulation of ChCs, DOCK7 knockdown/overexpression, co-immunoprecipitation of DOCK7 and ErbB4, morphological quantification of cartridges and boutons","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo genetic manipulation, single lab with defined morphological phenotype","pmids":["24440718"],"is_preprint":false},{"year":2014,"finding":"DOCK7 co-immunoprecipitates with c-Met in glioblastoma cells and this interaction is enhanced upon HGF stimulation in a manner dependent on the adaptor protein Gab1; Gab1 is required for HGF-induced DOCK7 and Rac1 activation and glioblastoma cell invasion. DOCK7 mediates serum- and HGF-induced GBM invasion via Rac activation.","method":"Co-immunoprecipitation (DOCK7 with c-Met, DOCK7 with Gab1), siRNA knockdown of DOCK7/Gab1, Rac1 GTPase activity assay, Matrigel and brain slice invasion assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GTPase activity assay, functional siRNA KD with invasion readout; single lab","pmids":["24518591"],"is_preprint":false},{"year":2009,"finding":"Loss-of-function mutations in DOCK7 (misty and moonlight alleles) that truncate the DOCK7 protein cause generalized hypopigmentation and white-spotting in mice, demonstrating a non-redundant role for DOCK7 in dermal and follicular melanocyte distribution/function.","method":"Forward genetic mapping, allele complementation test, sequencing of DOCK7 mutations in misty and moonlight mice, phenotypic characterization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mapping plus allele complementation establishing causality, two independent alleles confirming the same gene","pmids":["19202056"],"is_preprint":false},{"year":2012,"finding":"DOCK7 was identified as a binding partner of myosin VI (MVI) in neuronal PC12 cells by pull-down and mass spectrometry; endogenous MVI–DOCK7 interaction was confirmed by co-immunoprecipitation; the two proteins co-localize in interphase and dividing cells and in neurite outgrowths of primary hippocampal neurons.","method":"Pull-down + mass spectrometry, co-immunoprecipitation of endogenous proteins, co-localization by fluorescence microscopy","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS identification confirmed by co-IP, co-localization; no functional rescue or mutagenesis in this study","pmids":["22475431"],"is_preprint":false},{"year":2016,"finding":"Myosin VI (MVI) binds DOCK7 through its cargo domain RRL motif interacting with DOCK7 C-terminal M2 and DHR2 domains; MVI knockdown reduces Rac1 activity and decreases DOCK7 phosphorylation at Tyr1118, indicating that MVI contributes to DOCK7 activation; the MVI–DOCK7 interaction is required for NGF-stimulated protrusion formation in PC12 cells.","method":"Domain mapping by co-immunoprecipitation, MVI knockdown with Rac1 GTPase activity assay, pY1118-DOCK7 immunoblotting, NGF-stimulated differentiation assay, GFP-tagged cargo-domain dominant-negative overexpression","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level interaction mapping, functional KD phenotype, GTPase activity assay; single lab","pmids":["27018747"],"is_preprint":false},{"year":2017,"finding":"DOCK7 regulates postnatal neuroblast tangential migration along the rostral migratory stream via two distinct pathways: (1) a Rac-dependent pathway controlling leading process stability/growth likely through modulation of microtubule networks, and (2) a myosin phosphatase-RhoA-interacting protein (MYO9A/MPRIP)-dependent pathway regulating F-actin remodeling at the cell rear to promote somal translocation.","method":"In vivo DOCK7 knockdown by in utero electroporation, live imaging of neuroblast migration, F-actin and microtubule dynamics assays, Rac GTPase activity assays, dominant-negative pathway component expression","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic manipulation with live imaging and multiple pathway dissection experiments in a single focused study","pmids":["29089377"],"is_preprint":false},{"year":2017,"finding":"DOCK7 interacts with NBEAL2 (the gray platelet syndrome protein) in megakaryocytes and platelets; GPS-causing mutations in the NBEAL2 BEACH domain disrupt NBEAL2–DOCK7 interaction; DOCK7 is localized on the membrane of or in α-granules; platelets from GPS patients and Nbeal2-deficient mice are almost devoid of DOCK7, resulting in defective actin polymerization, platelet activation, and shape change.","method":"Co-immunoprecipitation (reverse), proximity ligation assay, subcellular fractionation/localization, GPS patient platelet analysis, Nbeal2 KO mouse platelet functional assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP validated by PLA, loss-of-function genetic model with defined functional platelet phenotype","pmids":["29187380"],"is_preprint":false},{"year":2021,"finding":"DOCK7 acts as a replication stress regulator: it is phosphorylated by ATR kinase upon replication stress and recruited by MDC1 to chromatin and replication forks; DOCK7-mediated Rac1/Cdc42 activation leads to PAK1 activation, which phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response; DOCK7 depletion sensitizes ovarian cancer cells to camptothecin.","method":"Chromatin fractionation, co-immunoprecipitation of DOCK7 with MDC1, phospho-site identification, Rac1/Cdc42 GTPase assays, PAK1 kinase assay, RPA1 phospho-mutant analysis, siRNA KD with camptothecin sensitivity assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical assays (fractionation, kinase cascade, phospho-mutant), Co-IP, functional KD; single lab but comprehensive","pmids":["33704464"],"is_preprint":false},{"year":2023,"finding":"A planar-polarized MYO6–DOCK7 axis spatially restricts RAC1 activity in mammary epithelial monolayers to drive cryptic lamellipodia extension in follower cells, thereby promoting tissue fluidification and cooperative collective motion; MYO6 activity is required upstream of DOCK7 for this polarized RAC1 activation.","method":"Live imaging of lamellipodia in monolayers, MYO6/DOCK7 knockdown, RAC1 activity biosensor (FRET or localization assay), collective migration tracking","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with live imaging and RAC1 activity readout; single lab, published in peer-reviewed journal","pmids":["37590133"],"is_preprint":false},{"year":2025,"finding":"The ErbB2–DOCK7 signaling axis mediates excessive neuronal process elongation induced by the ASD-linked Sema5A p.Arg676Cys variant; knockdown of DOCK7 or pharmacological inhibition of ErbB2 kinase reduces the aberrant process elongation and attenuates overactivation of downstream Rac1 and Cdc42 in primary cortical neurons and N1E-115 cells.","method":"shRNA knockdown of DOCK7, ErbB2 kinase inhibitor treatment, Rac1/Cdc42 GTPase activity assays, neuronal process length measurement in primary cortical neurons and N1E-115 cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with GTPase activity readout; single lab, no structural or reconstitution data","pmids":["41226692"],"is_preprint":false},{"year":2024,"finding":"DOCK7 packaged in tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) activates RAC1 in colorectal cancer (CRC) recipient cells, leading to AKT and FOXO1 phosphorylation and upregulation of ABCA1, which increases cholesterol efflux, membrane fluidity, and CRC cell motility/metastasis.","method":"EV isolation and LC-MS protein identification, siRNA knockdown of DOCK7 in TAM-EVs and CRC cells, RAC1 GTPase activity assay, AKT/FOXO1 phosphorylation immunoblotting, cholesterol efflux assay, Transwell migration and liver metastasis mouse model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EV-mediated transfer, GTPase activity assay, downstream signaling shown by immunoblot, functional metastasis model; single lab","pmids":["38385857"],"is_preprint":false}],"current_model":"DOCK7 is a DOCK180-family guanine nucleotide exchange factor (GEF) that activates Rac1 and Cdc42 (requiring membrane-anchored, prenylated GTPases for efficient catalysis via its DHR2 domain) downstream of receptor tyrosine kinases (ErbB2 phosphorylates DOCK7 at Tyr-1118 to activate it) and scaffold proteins (MDC1 recruits ATR-phosphorylated DOCK7 to replication forks), controlling neuronal axon specification via stathmin/Op18 phosphorylation, cortical neurogenesis via TACC3 antagonism and interkinetic nuclear migration, Schwann cell migration and myelination via Rac/Cdc42/JNK and Rho/ROCK signaling, interneuron morphogenesis, postnatal neuroblast tangential migration via parallel Rac-microtubule and MPRIP-RhoA-actin pathways, platelet α-granule biology via interaction with NBEAL2, and DNA replication stress responses via a DOCK7→Rac1/Cdc42→PAK1→RPA1 phosphorylation cascade."},"narrative":{"mechanistic_narrative":"DOCK7 is a DOCK180-family guanine nucleotide exchange factor that activates the Rho-family GTPases Rac1 and Cdc42 to drive cytoskeletal remodeling across neuronal development, cell migration, and the genotoxic stress response [PMID:16982419, PMID:23718289]. Its catalytic DHR2 domain efficiently exchanges nucleotide only on prenylated, membrane-anchored Cdc42/Rac1, and an N-terminal site within DHR2 binds GTP-loaded GTPase to recruit the domain to the membrane and create positive cooperativity that accelerates exchange [PMID:23718289]. DOCK7 activity is gated by upstream receptor and scaffold inputs: the NRG1 receptor ErbB2 directly binds and phosphorylates DOCK7 at Tyr-1118 to stimulate GEF activity and downstream JNK signaling [PMID:18426980], and DOCK7 is similarly engaged by ErbB4, RAGE, and the c-Met/Gab1 axis to channel receptor signals into Rac/Cdc42 activation [PMID:23254359, PMID:24440718, PMID:24518591]. In the nervous system DOCK7 specifies the axon through a Rac→stathmin/Op18 microtubule-destabilization pathway [PMID:16982419], controls cortical neurogenesis by antagonizing TACC3 to regulate interkinetic nuclear migration and progenitor fate [PMID:22842144], governs postnatal neuroblast tangential migration via parallel Rac–microtubule and MPRIP–RhoA–actin pathways [PMID:29089377], and negatively regulates Schwann cell differentiation and myelination by balancing Rac/Cdc42/JNK against Rho/ROCK signaling [PMID:21880919]. Beyond neurons, DOCK7 partners with myosin VI/MYO6 to spatially restrict Rac1 activity during protrusion formation and collective epithelial migration [PMID:27018747, PMID:37590133], with NBEAL2 to maintain platelet α-granule content and actin-dependent platelet activation [PMID:29187380], and acts in the DNA replication stress response by being recruited via MDC1 to replication forks, where DOCK7→Rac1/Cdc42→PAK1 signaling phosphorylates and stabilizes RPA1 [PMID:33704464].","teleology":[{"year":2006,"claim":"Established DOCK7 as a Rac activator with a defined developmental output by linking it to axon specification, answering what cellular process this GEF controls.","evidence":"shRNA knockdown, overexpression, localization, and phospho-stathmin assays in hippocampal neurons","pmids":["16982419"],"confidence":"High","gaps":["Did not define how DOCK7 itself is activated upstream","Direct GEF biochemistry on purified components not shown"]},{"year":2008,"claim":"Identified a direct upstream activator, showing ErbB2 phosphorylates DOCK7 at Tyr-1118 to switch on its GEF activity, connecting receptor tyrosine kinase signaling to Rac/Cdc42/JNK.","evidence":"Co-IP, Y1118F mutagenesis, GTPase pull-down assays, and Schwann cell migration rescue","pmids":["18426980"],"confidence":"High","gaps":["Structural basis of phospho-activation not resolved","Whether other RTKs use the same site untested at the time"]},{"year":2009,"claim":"Genetic loss-of-function alleles established a non-redundant in vivo requirement for DOCK7 in melanocyte distribution, extending its physiological roles beyond neurons.","evidence":"Forward genetic mapping and allele complementation of misty/moonlight mouse mutants","pmids":["19202056"],"confidence":"High","gaps":["Molecular pathway linking DOCK7 to melanocyte biology not defined","GTPase effector in this context unknown"]},{"year":2011,"claim":"Defined DOCK7 as a negative regulator of myelination, showing it tunes the balance between Rac/Cdc42/JNK and Rho/ROCK signaling to time Schwann cell differentiation.","evidence":"siRNA in primary Schwann cells, shRNA transgenic mice, GTPase activity assays, myelin thickness measurement","pmids":["21880919"],"confidence":"High","gaps":["Mechanism coupling DOCK7 to Rho/ROCK suppression unclear","Direct substrates beyond GTPases not identified"]},{"year":2012,"claim":"Expanded the partner repertoire and developmental reach, identifying TACC3 antagonism as the mechanism by which DOCK7 controls interkinetic nuclear migration and progenitor-versus-differentiation fate.","evidence":"In utero electroporation gain/loss-of-function, reciprocal Co-IP of DOCK7 and TACC3, INM and differentiation assays","pmids":["22842144"],"confidence":"High","gaps":["Whether GEF activity is required for TACC3 antagonism not separated","Direct vs. indirect binding to TACC3 not structurally defined"]},{"year":2012,"claim":"Implicated DOCK7 in receptor-driven cancer cell migration through a new receptor partner, RAGE, transducing signal to Cdc42.","evidence":"IP-LC-MS/MS interactor screen, Co-IP validation, Cdc42 activity assay, knockdown migration/morphology readouts","pmids":["23254359"],"confidence":"Medium","gaps":["Single-lab study without reciprocal in vivo validation","Direct binding interface with RAGE not mapped"]},{"year":2012,"claim":"Linked DOCK7 to the actin motor myosin VI, providing a candidate mechanism for spatially organizing its activity in neurons.","evidence":"Pull-down + mass spectrometry, endogenous Co-IP, and co-localization in PC12 cells and hippocampal neurons","pmids":["22475431"],"confidence":"Medium","gaps":["No functional consequence of the interaction shown in this study","No mutagenesis defining the binding interface"]},{"year":2013,"claim":"Resolved the catalytic mechanism, showing DHR2 is a GEF specific for prenylated, membrane-bound Cdc42/Rac1 and uses an allosteric GTP-loaded-GTPase site to drive cooperative, membrane-localized exchange.","evidence":"Liposome reconstitution, in vitro GEF assays with prenylated vs. non-prenylated GTPases, active-site and allosteric-site mutagenesis","pmids":["23718289"],"confidence":"High","gaps":["No full-length structure","How upstream phosphorylation modulates this catalytic cycle not integrated"]},{"year":2014,"claim":"Generalized the receptor-coupling principle to additional RTK contexts, showing DOCK7 activates ErbB4 in chandelier cells and engages c-Met via Gab1 to drive glioblastoma invasion.","evidence":"In utero electroporation manipulation and Co-IP for ErbB4; Co-IP, Gab1-dependence, Rac1 assay, and invasion assays for c-Met","pmids":["24440718","24518591"],"confidence":"Medium","gaps":["Whether DOCK7 phosphorylation site is conserved across these receptors not tested","Single-lab functional data per context"]},{"year":2016,"claim":"Established functional coupling between myosin VI and DOCK7, showing MYO6 promotes DOCK7 Tyr1118 phosphorylation and Rac1 activation required for NGF-induced protrusion.","evidence":"Domain-mapping Co-IP, MYO6 knockdown with Rac1 assay and pY1118 immunoblot, cargo-domain dominant-negative","pmids":["27018747"],"confidence":"Medium","gaps":["Mechanism by which MYO6 enhances Tyr1118 phosphorylation unclear","Single-lab study"]},{"year":2017,"claim":"Dissected DOCK7 control of neuroblast tangential migration into two molecularly distinct outputs, a Rac-microtubule leading-process pathway and an MPRIP-RhoA-actin rear pathway.","evidence":"In vivo knockdown by electroporation, live imaging, cytoskeletal dynamics and Rac assays, dominant-negative pathway components","pmids":["29089377"],"confidence":"High","gaps":["How DOCK7 partitions between the two pathways spatially not resolved","Upstream activator in migrating neuroblasts not identified"]},{"year":2017,"claim":"Revealed a non-cytoskeletal-developmental role in platelet biology, showing NBEAL2 binding retains DOCK7 in alpha-granules and supports actin-dependent platelet activation.","evidence":"Reciprocal Co-IP, proximity ligation, fractionation, GPS-patient and Nbeal2-KO mouse platelet assays","pmids":["29187380"],"confidence":"High","gaps":["Whether DOCK7 GEF activity is required for platelet phenotype not isolated","Granule cargo function vs. signaling role not fully separated"]},{"year":2021,"claim":"Placed DOCK7 in the DNA replication stress response, defining an ATR/MDC1-recruited DOCK7→Rac1/Cdc42→PAK1→RPA1 cascade that stabilizes chromatin-loaded RPA1.","evidence":"Chromatin fractionation, Co-IP with MDC1, phospho-site mapping, GTPase and PAK1 kinase assays, RPA1 phospho-mutant analysis, camptothecin sensitivity","pmids":["33704464"],"confidence":"High","gaps":["How a cytoplasmic GEF accesses chromatin GTPase pools not fully explained","Single-lab study without independent replication"]},{"year":2023,"claim":"Demonstrated spatial control of Rac1 in epithelia, showing a planar-polarized MYO6-DOCK7 axis restricts RAC1 to drive cryptic lamellipodia and collective tissue motion.","evidence":"Live imaging, MYO6/DOCK7 knockdown, RAC1 activity biosensor, collective migration tracking in mammary monolayers","pmids":["37590133"],"confidence":"Medium","gaps":["Single-lab study","Molecular basis of planar polarization of the axis not defined"]},{"year":2024,"claim":"Extended DOCK7 signaling to intercellular transfer, showing TAM-EV-delivered DOCK7 activates RAC1-AKT-FOXO1-ABCA1 to promote cholesterol efflux and colorectal cancer metastasis.","evidence":"EV isolation/LC-MS, DOCK7 knockdown, RAC1 assay, AKT/FOXO1 immunoblot, cholesterol efflux assay, liver metastasis model","pmids":["38385857"],"confidence":"Medium","gaps":["Single-lab study","Whether transferred DOCK7 retains canonical GEF mechanism in recipient cells untested"]},{"year":2025,"claim":"Connected the ErbB2-DOCK7 axis to a disease-linked variant, showing it mediates aberrant neuronal process elongation from an ASD-associated Sema5A mutation.","evidence":"shRNA knockdown, ErbB2 kinase inhibition, Rac1/Cdc42 assays, process-length measurement in cortical neurons and N1E-115 cells","pmids":["41226692"],"confidence":"Medium","gaps":["Single-lab study","Direct link from Sema5A to ErbB2-DOCK7 activation not biochemically defined"]},{"year":null,"claim":"How DOCK7's distinct upstream inputs (RTK phosphorylation, scaffold recruitment, motor coupling) are integrated to direct context-specific Rac versus Cdc42 outputs and select among parallel cytoskeletal pathways remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length structure linking regulatory inputs to the DHR2 catalytic cycle","No unified model for spatial partitioning between Rac-microtubule and Rho/MPRIP-actin outputs","Mechanism of nuclear/chromatin access for replication-stress role unclear"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[12]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["ERBB2","ERBB4","TACC3","MYO6","NBEAL2","MDC1","MET","AGER"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96N67","full_name":"Dedicator of cytokinesis protein 7","aliases":[],"length_aa":2140,"mass_kda":242.6,"function":"Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP. Does not have a GEF activity for CDC42. Required for STMN1 'Ser-15' phosphorylation during axon formation and consequently for neuronal polarization (PubMed:16982419). As part of the DISP complex, may regulate the association of septins with actin and thereby regulate the actin cytoskeleton (PubMed:29467281). Has a role in pigmentation (By similarity). Involved in the regulation of cortical neurogenesis through the control of radial glial cells (RGCs) proliferation versus differentiation; negatively regulates the basal-to-apical interkinetic nuclear migration of RGCs by antagonizing the microtubule growth-promoting function of TACC3 (By similarity)","subcellular_location":"Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q96N67/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOCK7","classification":"Not Classified","n_dependent_lines":84,"n_total_lines":1208,"dependency_fraction":0.0695364238410596},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000116641","cell_line_id":"CID000573","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cell_contact","grade":2}],"interactors":[{"gene":"LRCH3","stoichiometry":10.0},{"gene":"LRCH1","stoichiometry":10.0},{"gene":"RTN3","stoichiometry":4.0},{"gene":"MYO6","stoichiometry":4.0},{"gene":"RTN4","stoichiometry":4.0},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"DOCK6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000573","total_profiled":1310},"omim":[{"mim_id":"616223","title":"ANGIOPOIETIN-LIKE 8; ANGPTL8","url":"https://www.omim.org/entry/616223"},{"mim_id":"615859","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 23; DEE23","url":"https://www.omim.org/entry/615859"},{"mim_id":"615730","title":"DEDICATOR OF CYTOKINESIS 7; DOCK7","url":"https://www.omim.org/entry/615730"},{"mim_id":"613735","title":"BRAIN MALFORMATIONS WITH OR WITHOUT URINARY TRACT DEFECTS; BRMUTD","url":"https://www.omim.org/entry/613735"},{"mim_id":"611432","title":"DEDICATOR OF CYTOKINESIS 8; DOCK8","url":"https://www.omim.org/entry/611432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DOCK7"},"hgnc":{"alias_symbol":["KIAA1771","ZIR2"],"prev_symbol":[]},"alphafold":{"accession":"Q96N67","domains":[{"cath_id":"-","chopping":"259-411_459-465_517-550","consensus_level":"medium","plddt":86.9609,"start":259,"end":550},{"cath_id":"2.60.40.150","chopping":"561-732","consensus_level":"medium","plddt":89.9035,"start":561,"end":732},{"cath_id":"-","chopping":"736-858_983-1086","consensus_level":"medium","plddt":87.1048,"start":736,"end":1086},{"cath_id":"1.25.40.410","chopping":"1680-1754_1762-1836","consensus_level":"medium","plddt":82.7139,"start":1680,"end":1836},{"cath_id":"-","chopping":"1839-1991","consensus_level":"medium","plddt":86.3479,"start":1839,"end":1991},{"cath_id":"1.20.58.740","chopping":"1994-2118","consensus_level":"medium","plddt":81.1099,"start":1994,"end":2118}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N67","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N67-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N67-F1-predicted_aligned_error_v6.png","plddt_mean":73.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOCK7","jax_strain_url":"https://www.jax.org/strain/search?query=DOCK7"},"sequence":{"accession":"Q96N67","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96N67.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96N67/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N67"}},"corpus_meta":[{"pmid":"16982419","id":"PMC_16982419","title":"The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18.","date":"2006","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/16982419","citation_count":177,"is_preprint":false},{"pmid":"18426980","id":"PMC_18426980","title":"ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18426980","citation_count":113,"is_preprint":false},{"pmid":"22842144","id":"PMC_22842144","title":"DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis.","date":"2012","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22842144","citation_count":81,"is_preprint":false},{"pmid":"24440718","id":"PMC_24440718","title":"Regulation of chandelier cell cartridge and bouton development via DOCK7-mediated ErbB4 activation.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24440718","citation_count":43,"is_preprint":false},{"pmid":"21880919","id":"PMC_21880919","title":"The atypical Guanine-nucleotide exchange factor, dock7, negatively regulates schwann cell differentiation and myelination.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21880919","citation_count":41,"is_preprint":false},{"pmid":"24814191","id":"PMC_24814191","title":"Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24814191","citation_count":41,"is_preprint":false},{"pmid":"19202056","id":"PMC_19202056","title":"Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19202056","citation_count":36,"is_preprint":false},{"pmid":"24518591","id":"PMC_24518591","title":"Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation.","date":"2014","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24518591","citation_count":34,"is_preprint":false},{"pmid":"23254359","id":"PMC_23254359","title":"DOCK7 is a critical regulator of the RAGE-Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells.","date":"2012","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23254359","citation_count":34,"is_preprint":false},{"pmid":"38385857","id":"PMC_38385857","title":"Tumour-associated macrophage-derived DOCK7-enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38385857","citation_count":33,"is_preprint":false},{"pmid":"29187380","id":"PMC_29187380","title":"Nbeal2 interacts with Dock7, Sec16a, and Vac14.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29187380","citation_count":32,"is_preprint":false},{"pmid":"23718289","id":"PMC_23718289","title":"Prenylation and membrane localization of Cdc42 are essential for activation by DOCK7.","date":"2013","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23718289","citation_count":29,"is_preprint":false},{"pmid":"26744084","id":"PMC_26744084","title":"Association between the DOCK7, PCSK9 and GALNT2 Gene Polymorphisms and Serum Lipid levels.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26744084","citation_count":28,"is_preprint":false},{"pmid":"22475431","id":"PMC_22475431","title":"Dock7: a GEF for Rho-family GTPases and a novel myosin VI-binding partner in neuronal PC12 cells.","date":"2012","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/22475431","citation_count":27,"is_preprint":false},{"pmid":"27175020","id":"PMC_27175020","title":"CRISPR/Cas9-Mediated Insertion of loxP Sites in the Mouse Dock7 Gene Provides an Effective Alternative to Use of Targeted Embryonic Stem Cells.","date":"2016","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/27175020","citation_count":22,"is_preprint":false},{"pmid":"26493351","id":"PMC_26493351","title":"Association of the variants and haplotypes in the DOCK7, PCSK9 and GALNT2 genes and the risk of hyperlipidaemia.","date":"2015","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26493351","citation_count":19,"is_preprint":false},{"pmid":"29089377","id":"PMC_29089377","title":"Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29089377","citation_count":18,"is_preprint":false},{"pmid":"33704464","id":"PMC_33704464","title":"DOCK7 protects against replication stress by promoting RPA stability on chromatin.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33704464","citation_count":17,"is_preprint":false},{"pmid":"27018747","id":"PMC_27018747","title":"Interaction of myosin VI and its binding partner DOCK7 plays an important role in NGF-stimulated protrusion formation in PC12 cells.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27018747","citation_count":17,"is_preprint":false},{"pmid":"25086370","id":"PMC_25086370","title":"Oral administration of Nitraria retusa ethanolic extract enhances hepatic lipid metabolism in db/db mice model 'BKS.Cg-Dock7(m)+/+ Lepr(db/)J' through the modulation of lipogenesis-lipolysis balance.","date":"2014","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/25086370","citation_count":13,"is_preprint":false},{"pmid":"28821457","id":"PMC_28821457","title":"Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice.","date":"2017","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/28821457","citation_count":12,"is_preprint":false},{"pmid":"16982410","id":"PMC_16982410","title":"Nervous Rac: DOCK7 regulation of axon formation.","date":"2006","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/16982410","citation_count":9,"is_preprint":false},{"pmid":"37590133","id":"PMC_37590133","title":"A planar polarized MYO6-DOCK7-RAC1 axis promotes tissue fluidification in mammary epithelia.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37590133","citation_count":7,"is_preprint":false},{"pmid":"33471954","id":"PMC_33471954","title":"Characteristic facial features and cortical blindness distinguish the DOCK7-related epileptic encephalopathy.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33471954","citation_count":5,"is_preprint":false},{"pmid":"35806387","id":"PMC_35806387","title":"Homozygosity for a Novel DOCK7 Variant Due to Segmental Uniparental Isodisomy of Chromosome 1 Associated with Early Infantile Epileptic Encephalopathy (EIEE) and Cortical Visual Impairment.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35806387","citation_count":3,"is_preprint":false},{"pmid":"38257770","id":"PMC_38257770","title":"The Interaction between the DOCK7 Protein and the E2 Protein of Classical Swine Fever Virus Is Not Involved with Viral Replication or Pathogenicity.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/38257770","citation_count":2,"is_preprint":false},{"pmid":"41502932","id":"PMC_41502932","title":"Deletion of Dock7 Exons 3 and 4 Results in Reduced Trabecular Microarchitecture and a Decrease in Mineralization.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41502932","citation_count":1,"is_preprint":false},{"pmid":"36747801","id":"PMC_36747801","title":"A planar-polarized MYO6-DOCK7-RAC1 axis promotes tissue fluidification in mammary epithelia.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36747801","citation_count":0,"is_preprint":false},{"pmid":"41226692","id":"PMC_41226692","title":"The ErbB2-Dock7 Signaling Axis Mediates Excessive Cell Morphogenesis Induced by Autism Spectrum Disorder- and Intellectual Disability-Associated Sema5A p.Arg676Cys.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41226692","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33212,"output_tokens":8714,"usd":0.176024,"retried_sync":true},"stage2":{"model":"claude-opus-4-8","input_tokens":12957,"output_tokens":5145,"usd":0.096705,"stage2_stop_reason":"end_turn"},"total_usd":0.272729,"stage1_batch_id":"msgbatch_015cW3C55o5xm8EPaM1UvcZR","stage2_batch_id":"msgbatch_018NDJHPntdYJzBohpB6hHKo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"DOCK7 is a Rac GTPase activator that is asymmetrically distributed in unpolarized hippocampal neurons and selectively expressed in the nascent axon; DOCK7 knockdown prevents axon formation while overexpression induces multiple axons; DOCK7 and Rac activation lead to phosphorylation and inactivation of the microtubule destabilizing protein stathmin/Op18 in the nascent axon, establishing a DOCK7→Rac→stathmin/Op18 pathway for axon development.\",\n      \"method\": \"shRNA knockdown, overexpression, immunofluorescence localization, phospho-stathmin assays in hippocampal neurons\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, localization, phosphorylation assay) in a single focused study, replicated across conditions\",\n      \"pmids\": [\"16982419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The NRG1 receptor ErbB2 directly binds and phosphorylates DOCK7 at Tyr-1118, activating DOCK7 GEF activity toward Rac1 and Cdc42, which in turn activates JNK to promote Schwann cell migration; a Y1118F mutant of DOCK7 fails to transduce NRG1 signals.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Y1118F), Rho GTPase pull-down activity assays, siRNA knockdown, Schwann cell migration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct phosphorylation demonstrated with mutagenesis, reciprocal Co-IP, GTPase activity assays, and functional migration rescue\",\n      \"pmids\": [\"18426980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DOCK7 negatively regulates Schwann cell differentiation and onset of myelination: DOCK7 knockdown shortens Rac/Cdc42/JNK activation (negative regulator of myelination) and accelerates Rho/ROCK activation (positive regulator of myelination), resulting in enhanced myelin thickness in Dock7 shRNA transgenic mice.\",\n      \"method\": \"siRNA knockdown in primary Schwann cells, shRNA transgenic mouse generation, Rho GTPase activity assays, myelin thickness measurement\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo genetic KD with defined signaling and morphological readouts, consistent results across both systems\",\n      \"pmids\": [\"21880919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK7 interacts with the centrosome-associated protein TACC3 and antagonizes its microtubule growth-promoting function to control apically directed interkinetic nuclear migration of radial glial progenitor cells (RGCs), thereby regulating the switch from proliferative to differentiative divisions during cortical neurogenesis.\",\n      \"method\": \"In utero electroporation-based DOCK7 silencing/overexpression, co-immunoprecipitation of DOCK7 and TACC3, interkinetic nuclear migration assays, neuronal differentiation quantification\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying TACC3 as binding partner, combined with in vivo gain/loss-of-function and defined cellular phenotype (INM, progenitor vs. differentiation fate)\",\n      \"pmids\": [\"22842144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK7 binds to the cytoplasmic domain of RAGE (receptor for advanced glycation end-products) via co-immunoprecipitation/MS, and transduces RAGE signaling to Cdc42, resulting in formation of dendritic pseudopodia and promoting cancer cell migration.\",\n      \"method\": \"Immunoprecipitation–LC-MS/MS screen of RAGE cytoplasmic domain interactors, co-immunoprecipitation validation, Cdc42 activity assay, DOCK7 knockdown with cell migration and morphology readouts\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with MS identification, GTPase activity assay, and functional KD phenotype; single lab study\",\n      \"pmids\": [\"23254359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The DHR2 (GEF) domain of DOCK7 is a potent guanine nucleotide exchange factor for prenylated Cdc42 and Rac1 on membrane liposomes, but not for non-prenylated GTPases in solution; membrane localization of Cdc42/Rac1 is required for DOCK7-mediated activation. An N-terminal site within DHR2 (distinct from the catalytic active site) preferentially binds GTP-loaded Cdc42/Rac1 and recruits DHR2 to the membrane, creating positive cooperativity that accelerates nucleotide exchange.\",\n      \"method\": \"Liposome reconstitution assay, in vitro GEF activity assay with prenylated vs. non-prenylated GTPases, site-directed mutagenesis to identify GTPase-selectivity residues\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with liposomes, mutagenesis of catalytic and allosteric sites, multiple orthogonal enzymatic assays\",\n      \"pmids\": [\"23718289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOCK7 functions as a cytoplasmic activator of the ErbB4 receptor tyrosine kinase in chandelier cells (ChCs); DOCK7 modulates ErbB4 activity and is required for chandelier cell cartridge and bouton development in vivo.\",\n      \"method\": \"In utero electroporation-based genetic labeling and manipulation of ChCs, DOCK7 knockdown/overexpression, co-immunoprecipitation of DOCK7 and ErbB4, morphological quantification of cartridges and boutons\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo genetic manipulation, single lab with defined morphological phenotype\",\n      \"pmids\": [\"24440718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOCK7 co-immunoprecipitates with c-Met in glioblastoma cells and this interaction is enhanced upon HGF stimulation in a manner dependent on the adaptor protein Gab1; Gab1 is required for HGF-induced DOCK7 and Rac1 activation and glioblastoma cell invasion. DOCK7 mediates serum- and HGF-induced GBM invasion via Rac activation.\",\n      \"method\": \"Co-immunoprecipitation (DOCK7 with c-Met, DOCK7 with Gab1), siRNA knockdown of DOCK7/Gab1, Rac1 GTPase activity assay, Matrigel and brain slice invasion assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GTPase activity assay, functional siRNA KD with invasion readout; single lab\",\n      \"pmids\": [\"24518591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss-of-function mutations in DOCK7 (misty and moonlight alleles) that truncate the DOCK7 protein cause generalized hypopigmentation and white-spotting in mice, demonstrating a non-redundant role for DOCK7 in dermal and follicular melanocyte distribution/function.\",\n      \"method\": \"Forward genetic mapping, allele complementation test, sequencing of DOCK7 mutations in misty and moonlight mice, phenotypic characterization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping plus allele complementation establishing causality, two independent alleles confirming the same gene\",\n      \"pmids\": [\"19202056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK7 was identified as a binding partner of myosin VI (MVI) in neuronal PC12 cells by pull-down and mass spectrometry; endogenous MVI–DOCK7 interaction was confirmed by co-immunoprecipitation; the two proteins co-localize in interphase and dividing cells and in neurite outgrowths of primary hippocampal neurons.\",\n      \"method\": \"Pull-down + mass spectrometry, co-immunoprecipitation of endogenous proteins, co-localization by fluorescence microscopy\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS identification confirmed by co-IP, co-localization; no functional rescue or mutagenesis in this study\",\n      \"pmids\": [\"22475431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myosin VI (MVI) binds DOCK7 through its cargo domain RRL motif interacting with DOCK7 C-terminal M2 and DHR2 domains; MVI knockdown reduces Rac1 activity and decreases DOCK7 phosphorylation at Tyr1118, indicating that MVI contributes to DOCK7 activation; the MVI–DOCK7 interaction is required for NGF-stimulated protrusion formation in PC12 cells.\",\n      \"method\": \"Domain mapping by co-immunoprecipitation, MVI knockdown with Rac1 GTPase activity assay, pY1118-DOCK7 immunoblotting, NGF-stimulated differentiation assay, GFP-tagged cargo-domain dominant-negative overexpression\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level interaction mapping, functional KD phenotype, GTPase activity assay; single lab\",\n      \"pmids\": [\"27018747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DOCK7 regulates postnatal neuroblast tangential migration along the rostral migratory stream via two distinct pathways: (1) a Rac-dependent pathway controlling leading process stability/growth likely through modulation of microtubule networks, and (2) a myosin phosphatase-RhoA-interacting protein (MYO9A/MPRIP)-dependent pathway regulating F-actin remodeling at the cell rear to promote somal translocation.\",\n      \"method\": \"In vivo DOCK7 knockdown by in utero electroporation, live imaging of neuroblast migration, F-actin and microtubule dynamics assays, Rac GTPase activity assays, dominant-negative pathway component expression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic manipulation with live imaging and multiple pathway dissection experiments in a single focused study\",\n      \"pmids\": [\"29089377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DOCK7 interacts with NBEAL2 (the gray platelet syndrome protein) in megakaryocytes and platelets; GPS-causing mutations in the NBEAL2 BEACH domain disrupt NBEAL2–DOCK7 interaction; DOCK7 is localized on the membrane of or in α-granules; platelets from GPS patients and Nbeal2-deficient mice are almost devoid of DOCK7, resulting in defective actin polymerization, platelet activation, and shape change.\",\n      \"method\": \"Co-immunoprecipitation (reverse), proximity ligation assay, subcellular fractionation/localization, GPS patient platelet analysis, Nbeal2 KO mouse platelet functional assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP validated by PLA, loss-of-function genetic model with defined functional platelet phenotype\",\n      \"pmids\": [\"29187380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DOCK7 acts as a replication stress regulator: it is phosphorylated by ATR kinase upon replication stress and recruited by MDC1 to chromatin and replication forks; DOCK7-mediated Rac1/Cdc42 activation leads to PAK1 activation, which phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response; DOCK7 depletion sensitizes ovarian cancer cells to camptothecin.\",\n      \"method\": \"Chromatin fractionation, co-immunoprecipitation of DOCK7 with MDC1, phospho-site identification, Rac1/Cdc42 GTPase assays, PAK1 kinase assay, RPA1 phospho-mutant analysis, siRNA KD with camptothecin sensitivity assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical assays (fractionation, kinase cascade, phospho-mutant), Co-IP, functional KD; single lab but comprehensive\",\n      \"pmids\": [\"33704464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A planar-polarized MYO6–DOCK7 axis spatially restricts RAC1 activity in mammary epithelial monolayers to drive cryptic lamellipodia extension in follower cells, thereby promoting tissue fluidification and cooperative collective motion; MYO6 activity is required upstream of DOCK7 for this polarized RAC1 activation.\",\n      \"method\": \"Live imaging of lamellipodia in monolayers, MYO6/DOCK7 knockdown, RAC1 activity biosensor (FRET or localization assay), collective migration tracking\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with live imaging and RAC1 activity readout; single lab, published in peer-reviewed journal\",\n      \"pmids\": [\"37590133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The ErbB2–DOCK7 signaling axis mediates excessive neuronal process elongation induced by the ASD-linked Sema5A p.Arg676Cys variant; knockdown of DOCK7 or pharmacological inhibition of ErbB2 kinase reduces the aberrant process elongation and attenuates overactivation of downstream Rac1 and Cdc42 in primary cortical neurons and N1E-115 cells.\",\n      \"method\": \"shRNA knockdown of DOCK7, ErbB2 kinase inhibitor treatment, Rac1/Cdc42 GTPase activity assays, neuronal process length measurement in primary cortical neurons and N1E-115 cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with GTPase activity readout; single lab, no structural or reconstitution data\",\n      \"pmids\": [\"41226692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DOCK7 packaged in tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) activates RAC1 in colorectal cancer (CRC) recipient cells, leading to AKT and FOXO1 phosphorylation and upregulation of ABCA1, which increases cholesterol efflux, membrane fluidity, and CRC cell motility/metastasis.\",\n      \"method\": \"EV isolation and LC-MS protein identification, siRNA knockdown of DOCK7 in TAM-EVs and CRC cells, RAC1 GTPase activity assay, AKT/FOXO1 phosphorylation immunoblotting, cholesterol efflux assay, Transwell migration and liver metastasis mouse model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EV-mediated transfer, GTPase activity assay, downstream signaling shown by immunoblot, functional metastasis model; single lab\",\n      \"pmids\": [\"38385857\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOCK7 is a DOCK180-family guanine nucleotide exchange factor (GEF) that activates Rac1 and Cdc42 (requiring membrane-anchored, prenylated GTPases for efficient catalysis via its DHR2 domain) downstream of receptor tyrosine kinases (ErbB2 phosphorylates DOCK7 at Tyr-1118 to activate it) and scaffold proteins (MDC1 recruits ATR-phosphorylated DOCK7 to replication forks), controlling neuronal axon specification via stathmin/Op18 phosphorylation, cortical neurogenesis via TACC3 antagonism and interkinetic nuclear migration, Schwann cell migration and myelination via Rac/Cdc42/JNK and Rho/ROCK signaling, interneuron morphogenesis, postnatal neuroblast tangential migration via parallel Rac-microtubule and MPRIP-RhoA-actin pathways, platelet α-granule biology via interaction with NBEAL2, and DNA replication stress responses via a DOCK7→Rac1/Cdc42→PAK1→RPA1 phosphorylation cascade.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOCK7 is a DOCK180-family guanine nucleotide exchange factor that activates the Rho-family GTPases Rac1 and Cdc42 to drive cytoskeletal remodeling across neuronal development, cell migration, and the genotoxic stress response [#0, #5]. Its catalytic DHR2 domain efficiently exchanges nucleotide only on prenylated, membrane-anchored Cdc42/Rac1, and an N-terminal site within DHR2 binds GTP-loaded GTPase to recruit the domain to the membrane and create positive cooperativity that accelerates exchange [#5]. DOCK7 activity is gated by upstream receptor and scaffold inputs: the NRG1 receptor ErbB2 directly binds and phosphorylates DOCK7 at Tyr-1118 to stimulate GEF activity and downstream JNK signaling [#1], and DOCK7 is similarly engaged by ErbB4, RAGE, and the c-Met/Gab1 axis to channel receptor signals into Rac/Cdc42 activation [#4, #6, #7]. In the nervous system DOCK7 specifies the axon through a Rac\\u2192stathmin/Op18 microtubule-destabilization pathway [#0], controls cortical neurogenesis by antagonizing TACC3 to regulate interkinetic nuclear migration and progenitor fate [#3], governs postnatal neuroblast tangential migration via parallel Rac\\u2013microtubule and MPRIP\\u2013RhoA\\u2013actin pathways [#11], and negatively regulates Schwann cell differentiation and myelination by balancing Rac/Cdc42/JNK against Rho/ROCK signaling [#2]. Beyond neurons, DOCK7 partners with myosin VI/MYO6 to spatially restrict Rac1 activity during protrusion formation and collective epithelial migration [#10, #14], with NBEAL2 to maintain platelet \\u03b1-granule content and actin-dependent platelet activation [#12], and acts in the DNA replication stress response by being recruited via MDC1 to replication forks, where DOCK7\\u2192Rac1/Cdc42\\u2192PAK1 signaling phosphorylates and stabilizes RPA1 [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established DOCK7 as a Rac activator with a defined developmental output by linking it to axon specification, answering what cellular process this GEF controls.\",\n      \"evidence\": \"shRNA knockdown, overexpression, localization, and phospho-stathmin assays in hippocampal neurons\",\n      \"pmids\": [\"16982419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how DOCK7 itself is activated upstream\", \"Direct GEF biochemistry on purified components not shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a direct upstream activator, showing ErbB2 phosphorylates DOCK7 at Tyr-1118 to switch on its GEF activity, connecting receptor tyrosine kinase signaling to Rac/Cdc42/JNK.\",\n      \"evidence\": \"Co-IP, Y1118F mutagenesis, GTPase pull-down assays, and Schwann cell migration rescue\",\n      \"pmids\": [\"18426980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of phospho-activation not resolved\", \"Whether other RTKs use the same site untested at the time\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic loss-of-function alleles established a non-redundant in vivo requirement for DOCK7 in melanocyte distribution, extending its physiological roles beyond neurons.\",\n      \"evidence\": \"Forward genetic mapping and allele complementation of misty/moonlight mouse mutants\",\n      \"pmids\": [\"19202056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking DOCK7 to melanocyte biology not defined\", \"GTPase effector in this context unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined DOCK7 as a negative regulator of myelination, showing it tunes the balance between Rac/Cdc42/JNK and Rho/ROCK signaling to time Schwann cell differentiation.\",\n      \"evidence\": \"siRNA in primary Schwann cells, shRNA transgenic mice, GTPase activity assays, myelin thickness measurement\",\n      \"pmids\": [\"21880919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling DOCK7 to Rho/ROCK suppression unclear\", \"Direct substrates beyond GTPases not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanded the partner repertoire and developmental reach, identifying TACC3 antagonism as the mechanism by which DOCK7 controls interkinetic nuclear migration and progenitor-versus-differentiation fate.\",\n      \"evidence\": \"In utero electroporation gain/loss-of-function, reciprocal Co-IP of DOCK7 and TACC3, INM and differentiation assays\",\n      \"pmids\": [\"22842144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GEF activity is required for TACC3 antagonism not separated\", \"Direct vs. indirect binding to TACC3 not structurally defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Implicated DOCK7 in receptor-driven cancer cell migration through a new receptor partner, RAGE, transducing signal to Cdc42.\",\n      \"evidence\": \"IP-LC-MS/MS interactor screen, Co-IP validation, Cdc42 activity assay, knockdown migration/morphology readouts\",\n      \"pmids\": [\"23254359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without reciprocal in vivo validation\", \"Direct binding interface with RAGE not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked DOCK7 to the actin motor myosin VI, providing a candidate mechanism for spatially organizing its activity in neurons.\",\n      \"evidence\": \"Pull-down + mass spectrometry, endogenous Co-IP, and co-localization in PC12 cells and hippocampal neurons\",\n      \"pmids\": [\"22475431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the interaction shown in this study\", \"No mutagenesis defining the binding interface\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the catalytic mechanism, showing DHR2 is a GEF specific for prenylated, membrane-bound Cdc42/Rac1 and uses an allosteric GTP-loaded-GTPase site to drive cooperative, membrane-localized exchange.\",\n      \"evidence\": \"Liposome reconstitution, in vitro GEF assays with prenylated vs. non-prenylated GTPases, active-site and allosteric-site mutagenesis\",\n      \"pmids\": [\"23718289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure\", \"How upstream phosphorylation modulates this catalytic cycle not integrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Generalized the receptor-coupling principle to additional RTK contexts, showing DOCK7 activates ErbB4 in chandelier cells and engages c-Met via Gab1 to drive glioblastoma invasion.\",\n      \"evidence\": \"In utero electroporation manipulation and Co-IP for ErbB4; Co-IP, Gab1-dependence, Rac1 assay, and invasion assays for c-Met\",\n      \"pmids\": [\"24440718\", \"24518591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DOCK7 phosphorylation site is conserved across these receptors not tested\", \"Single-lab functional data per context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established functional coupling between myosin VI and DOCK7, showing MYO6 promotes DOCK7 Tyr1118 phosphorylation and Rac1 activation required for NGF-induced protrusion.\",\n      \"evidence\": \"Domain-mapping Co-IP, MYO6 knockdown with Rac1 assay and pY1118 immunoblot, cargo-domain dominant-negative\",\n      \"pmids\": [\"27018747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MYO6 enhances Tyr1118 phosphorylation unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected DOCK7 control of neuroblast tangential migration into two molecularly distinct outputs, a Rac-microtubule leading-process pathway and an MPRIP-RhoA-actin rear pathway.\",\n      \"evidence\": \"In vivo knockdown by electroporation, live imaging, cytoskeletal dynamics and Rac assays, dominant-negative pathway components\",\n      \"pmids\": [\"29089377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DOCK7 partitions between the two pathways spatially not resolved\", \"Upstream activator in migrating neuroblasts not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-cytoskeletal-developmental role in platelet biology, showing NBEAL2 binding retains DOCK7 in alpha-granules and supports actin-dependent platelet activation.\",\n      \"evidence\": \"Reciprocal Co-IP, proximity ligation, fractionation, GPS-patient and Nbeal2-KO mouse platelet assays\",\n      \"pmids\": [\"29187380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOCK7 GEF activity is required for platelet phenotype not isolated\", \"Granule cargo function vs. signaling role not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed DOCK7 in the DNA replication stress response, defining an ATR/MDC1-recruited DOCK7\\u2192Rac1/Cdc42\\u2192PAK1\\u2192RPA1 cascade that stabilizes chromatin-loaded RPA1.\",\n      \"evidence\": \"Chromatin fractionation, Co-IP with MDC1, phospho-site mapping, GTPase and PAK1 kinase assays, RPA1 phospho-mutant analysis, camptothecin sensitivity\",\n      \"pmids\": [\"33704464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a cytoplasmic GEF accesses chromatin GTPase pools not fully explained\", \"Single-lab study without independent replication\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated spatial control of Rac1 in epithelia, showing a planar-polarized MYO6-DOCK7 axis restricts RAC1 to drive cryptic lamellipodia and collective tissue motion.\",\n      \"evidence\": \"Live imaging, MYO6/DOCK7 knockdown, RAC1 activity biosensor, collective migration tracking in mammary monolayers\",\n      \"pmids\": [\"37590133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Molecular basis of planar polarization of the axis not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended DOCK7 signaling to intercellular transfer, showing TAM-EV-delivered DOCK7 activates RAC1-AKT-FOXO1-ABCA1 to promote cholesterol efflux and colorectal cancer metastasis.\",\n      \"evidence\": \"EV isolation/LC-MS, DOCK7 knockdown, RAC1 assay, AKT/FOXO1 immunoblot, cholesterol efflux assay, liver metastasis model\",\n      \"pmids\": [\"38385857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether transferred DOCK7 retains canonical GEF mechanism in recipient cells untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected the ErbB2-DOCK7 axis to a disease-linked variant, showing it mediates aberrant neuronal process elongation from an ASD-associated Sema5A mutation.\",\n      \"evidence\": \"shRNA knockdown, ErbB2 kinase inhibition, Rac1/Cdc42 assays, process-length measurement in cortical neurons and N1E-115 cells\",\n      \"pmids\": [\"41226692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct link from Sema5A to ErbB2-DOCK7 activation not biochemically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DOCK7's distinct upstream inputs (RTK phosphorylation, scaffold recruitment, motor coupling) are integrated to direct context-specific Rac versus Cdc42 outputs and select among parallel cytoskeletal pathways remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure linking regulatory inputs to the DHR2 catalytic cycle\", \"No unified model for spatial partitioning between Rac-microtubule and Rho/MPRIP-actin outputs\", \"Mechanism of nuclear/chromatin access for replication-stress role unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [0, 1, 5, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ERBB2\", \"ERBB4\", \"TACC3\", \"MYO6\", \"NBEAL2\", \"MDC1\", \"MET\", \"AGER\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}