{"gene":"DOCK5","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2021,"finding":"Cryo-EM structure of the active ELMO1-DOCK5 complex bound to Rac1 at 3.8-Å resolution revealed that the C-terminal region of ELMO1 (including the PH domain) aids in binding of the catalytic DHR-2 domain of DOCK5 to nucleotide-free Rac1, and a complex α-helical scaffold between ELMO1 and DOCK5 stabilizes Rac1 binding. Mutagenesis confirmed that the ELMO1 PH domain enhances DOCK5 GEF activity through specific interactions with Rac1.","method":"Cryo-EM structure determination + mutagenesis + in vitro GEF activity assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure combined with mutagenesis and biochemical GEF assay in a single rigorous study","pmids":["34290093"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of DOCK5/ELMO1 alone and in complex with RhoG and Rac1 showed that DOCK5/ELMO1 adopts a closed (autoinhibited) conformation in the apo state. RhoG binds simultaneously to both ELMO1 and DOCK5 and facilitates a closed-to-open conformational transition, enhancing DOCK5 GEF activity toward Rac1. SPR assays confirmed RhoG increases DOCK5/ELMO1 binding affinity for Rac1. The DOCK5 phosphatidylinositol(3,4,5)-trisphosphate binding site aligns with the RhoG C-terminal lipidation site, suggesting simultaneous membrane and RhoG binding.","method":"Cryo-EM structure determination + surface plasmon resonance + in vitro GEF activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple cryo-EM structures with biochemical SPR and GEF assays, multiple orthogonal methods in one rigorous study","pmids":["38857861"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM on lipid membrane-coated grids revealed a new conformation in which DOCK5, ELMO1, RhoG, and Rac1 are symmetrically flattened on a plane on the lipid membrane, driven by rotation at each DOCK5•ELMO1 hinge site through membrane interactions. Biochemical and cellular experiments showed that conformational changes driven by acidic lipids regulate DOCK5•ELMO1 GEF activity on the plasma membrane and are essential for downstream signaling.","method":"Cryo-EM with lipid membrane grid + biochemical GEF assay + cellular experiments","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural determination with orthogonal biochemical and cellular validation in one study","pmids":["41233496"],"is_preprint":false},{"year":2014,"finding":"DOCK5 functions as a GEF-independent signaling adaptor in mast cell degranulation: its Rac GEF activity is not required for this process. Instead, DOCK5 associates with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β downstream of FcεRI aggregation. Disruption of DOCK5-Nck2-Akt interactions severely impaired microtubule formation and degranulation. DOCK5-deficient mice are resistant to systemic and cutaneous anaphylaxis.","method":"Co-immunoprecipitation, DOCK5-deficient mice (in vivo anaphylaxis models), interaction-disruption mutants, microtubule dynamics assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vivo KO mice with defined phenotype, and multiple mechanistic readouts across multiple orthogonal methods","pmids":["24913231"],"is_preprint":false},{"year":2016,"finding":"DOCK5 is recruited to focal adhesions (FAs) in HeLa cells, and this recruitment is restricted by GIT2, which is targeted to FAs by Rho-ROCK signaling and actomyosin contractility. GIT2 inhibits the DOCK5-Crk interaction; depletion of GIT2 promotes DOCK5-dependent activation of the Crk-p130Cas cascade, leading to Rac1-mediated lamellipodial protrusion and FA turnover. DOCK5 inhibition attenuates invasion and metastasis of MDA-MB-231 cells and prolongs mouse lifespan in a xenograft model.","method":"siRNA knockdown, Co-immunoprecipitation, live-cell imaging of FA dynamics, mouse metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis by depletion/rescue, in vivo metastasis model, multiple orthogonal methods","pmids":["27669437"],"is_preprint":false},{"year":2016,"finding":"Tensin 3 is a binding partner of Dock5 in osteoclasts, identified by proteomic analysis. Tensin 3 and Dock5 co-localize at the osteoclast podosome belt but not at individual podosomes. Tensin 3 increases Dock5 exchange activity toward Rac. Suppression of tensin 3 destabilizes podosome organization, delocalizes Dock5, and severely reduces osteoclast resorption activity.","method":"Proteomics/mass spectrometry, Co-IP, super-resolution microscopy, siRNA knockdown, in vitro GEF assay, bone resorption assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification confirmed by Co-IP, GEF assay, super-resolution imaging, and functional KD, multiple orthogonal methods","pmids":["27505886"],"is_preprint":false},{"year":2019,"finding":"Dock5 knockout osteoclasts display reduced acetylated tubulin levels, decreased microtubule growth phase length and duration, and impaired sealing zone formation. Dock5 regulates microtubule dynamic instability through both Rac-dependent pathways and a Rac-independent pathway involving GSK3β inhibitory Ser9 phosphorylation downstream of Akt. Dock5 does not act through direct interaction with polymerized tubulin.","method":"Dock5 knockout osteoclasts, Rac inhibitors (pharmacological), western blotting for GSK3β phosphorylation, microtubule dynamics imaging","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined microtubule phenotype and pathway placement (GSK3β/Akt), single lab with two orthogonal methods","pmids":["31461543"],"is_preprint":false},{"year":2019,"finding":"DOCK5 interacts with Raptor (mTORC1 scaffold) in hepatocytes, and this interaction is required for DOCK5-mediated regulation of hepatic glucose production. DOCK5 overexpression inhibits mTOR/S6K1 phosphorylation and reduces Raptor protein expression, improving insulin sensitivity. Deletion of DOCK5 activates the mTOR(Raptor)/S6K1 pathway and dysregulates glucose metabolism in mice on high-fat diet. In liver-specific Raptor knockout mice, effects of DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated.","method":"Co-immunoprecipitation (DOCK5-Raptor), DOCK5 KO and overexpression mice, AAV8/adenovirus-mediated DOCK5 knockdown, liver-specific Raptor KO epistasis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis (Raptor KO rescue), in vivo KO and OE with defined metabolic phenotypes, multiple orthogonal methods","pmids":["31885214"],"is_preprint":false},{"year":2008,"finding":"Human DOCK5 co-immunoprecipitates with CrkII and CrkL via their N-terminal SH3 domains. DOCK5 requires CrkII/CrkL to restore cell spreading when expressed with DOCK5 siRNA. The DOCK5 C-terminal region (Met1738-Gln1870) contains proline-rich sites that mediate CrkL binding; deletion of aa 1832-1870 strongly reduces DOCK5-CrkL co-immunoprecipitation. GFP-tagged DOCK5 localizes to the membrane of Caco-2 cells spreading on collagen IV. Combined DOCK1/DOCK5 siRNA synergistically inhibits spreading, migration, and lamellipodial extension.","method":"Co-immunoprecipitation, siRNA knockdown, rescue with siRNA-resistant cDNA, GFP live imaging, domain-deletion mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain-deletion mapping, functional rescue experiments, localization, single lab","pmids":["19004829"],"is_preprint":false},{"year":2007,"finding":"Morpholino knockdown of Dock5 (and Dock1) in zebrafish embryos blocks fusion of embryonic fast-twitch myoblasts, establishing a functional requirement for Dock5 in myoblast fusion. Crk and Crkl adaptor proteins (known physical interactors of Dock proteins) are also required for this process.","method":"Morpholino antisense knockdown in zebrafish embryo, histological analysis of myoblast fusion","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with defined cellular phenotype in an in vivo vertebrate model, single lab","pmids":["17670792"],"is_preprint":false},{"year":2008,"finding":"A spontaneous in-frame 27-bp deletion in exon 15 of mouse Dock5 (removing aa 506-514 in the DHR1 domain) causes near-complete loss of DOCK5 protein in lens despite normal mRNA levels, leading to cataract and lens rupture. DOCK5 protein is normally localized to the cytoplasm of anterior lens epithelial cells and weakly in lens fiber cells.","method":"Positional cloning, RT-PCR, immunohistochemistry, protein expression analysis in mutant vs. wild-type lens","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mutation with direct protein localization and defined phenotypic consequence, single study","pmids":["18396277"],"is_preprint":false},{"year":2019,"finding":"Dock5 deficiency in mice reduces follicular and marginal zone B cells. In Dock5 KO B cells, BCR signaling molecules CD19 and Btk show reduced activation upon stimulation, and F-actin levels decrease after stimulation. TIRF microscopy and immunoblot analyses established that Dock5 regulates peripheral B cell differentiation by controlling the CD19-Btk signaling axis and actin reorganization.","method":"Dock5 KO mice, TIRF microscopy, immunoblot, flow cytometry","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with defined B cell phenotype and mechanistic pathway placement, single lab","pmids":["30661670"],"is_preprint":false},{"year":2023,"finding":"Podocyte-specific deletion of Dock5 exacerbates podocyte injury and glomerular pathology in proteinuric kidney disease. Mechanistically, Dock5 deficiency upregulates LXRα in an m6A-dependent manner, which increases CD36-mediated fatty acid uptake in podocytes, causing lipotoxicity.","method":"Podocyte-specific Dock5 KO mice, m6A modification analysis, CD36/LXRα expression and functional assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular pathway (m6A/LXRα/CD36), single lab","pmids":["38161229"],"is_preprint":false},{"year":2024,"finding":"Liraglutide directly binds to unconventional myosin 1c (Myo1c) at arginine 93, enhancing the Myo1c/Dock5 interaction. This promotes Dock5 expression (by targeting its promoter) and improves proliferation, migration, and adhesion of keratinocytes to accelerate diabetic wound healing. The healing effects of liraglutide are abrogated in Dock5 keratinocyte-specific knockout mice.","method":"Dock5 keratinocyte-specific KO mice, binding assays (liraglutide-Myo1c), co-immunoprecipitation (Myo1c/Dock5), promoter analysis, in vivo diabetic wound healing model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype, Co-IP of Myo1c/Dock5 interaction, direct binding mapping, single lab","pmids":["39159301"],"is_preprint":false},{"year":2024,"finding":"Dock5 signalosome molecules (including Dock5 and its adaptor Elmo2) control process elongation in N1E-115 neuronal cells. CRISPR/CasRx knockdown of Dock5 or Elmo2, or transfection of the Dock5-Elmo2 interaction region, recovered ASD-associated Sema5A (p.R676C)-induced process elongation and reduced JNK activation, establishing Dock5-Elmo2 signalosome as a downstream mediator of Sema5A-induced neuronal morphogenesis.","method":"CRISPR/CasRx knockdown, JNK phosphorylation assay, dominant-negative interaction domain transfection, cell morphology analysis","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KD with defined neuronal morphology phenotype and JNK pathway placement, single lab","pmids":["38666924"],"is_preprint":false},{"year":2025,"finding":"DOCK5 is essential for YAP/TAZ nuclear localization in TNBC cells and for resistance to MEK inhibitor Binimetinib. DOCK5-deficient TNBC cells exhibit defects in FA morphogenesis and fail to generate a stable polarized leading edge. Mechanistically, DOCK5's role requires both its RacGEF activity and its ability to scaffold NCK/AKT at focal adhesions.","method":"Multiplexed genetic screens (quantitative imaging), DOCK5 knockdown, FA morphology and cell polarity assays, YAP/TAZ localization assay, drug resistance assay","journal":"Molecular omics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiplexed genetic screens with defined cellular phenotypes and mechanistic dissection (RacGEF vs scaffold), single lab","pmids":["40353692"],"is_preprint":false},{"year":2013,"finding":"Dock1 and Dock5 are expressed in podocytes, but mice lacking Dock1 and/or Dock5 show no essential defect in glomerular filtration barrier formation or maintenance. Dock1 single KO mice were not protected from LPS-induced podocyte effacement. This is a negative finding: Dock1 and Dock5 are not the critical exchange factors regulating Rac activity during establishment and maintenance of the glomerular barrier.","method":"Dock1 and Dock5 KO mice, kidney histology, LPS-induced podocyte effacement model","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined negative phenotypic readout, single lab; negative result explicitly reported","pmids":["24365888"],"is_preprint":false}],"current_model":"DOCK5 is an atypical guanine nucleotide exchange factor (GEF) for Rac1 whose catalytic DHR-2 domain is activated by ELMO1 (which enhances Rac1 binding via its PH domain) and by RhoG-driven allosteric opening of the closed DOCK5•ELMO1 complex; on the plasma membrane, acidic lipid-driven conformational changes further regulate its GEF activity. Beyond its GEF function, DOCK5 acts as a scaffold—associating with CrkII/CrkL, Nck2/AKT, tensin 3, Raptor, and Myo1c—to regulate diverse processes including focal adhesion turnover and Rac1-mediated lamellipodial protrusion, mast cell degranulation via GSK3β-dependent microtubule dynamics, osteoclast podosome belt organization and bone resorption, hepatic insulin sensitivity through mTORC1/Raptor suppression, YAP/TAZ nuclear localization in breast cancer cells, and B cell receptor signaling and actin reorganization."},"narrative":{"mechanistic_narrative":"DOCK5 is an atypical guanine nucleotide exchange factor (GEF) for Rac1 that also functions as a multivalent signaling scaffold, coupling receptor and adhesion signals to actin remodeling and cytoskeletal dynamics across diverse cell types [PMID:38857861, PMID:19004829]. Its catalytic DHR-2 domain engages nucleotide-free Rac1 within an ELMO1-stabilized α-helical scaffold, where the ELMO1 PH domain enhances GEF activity through direct Rac1 contacts [PMID:34290093]; in the apo state the DOCK5/ELMO1 complex is autoinhibited (closed), and RhoG binds both subunits simultaneously to drive a closed-to-open transition that raises Rac1 affinity and GEF output [PMID:38857861]. On the plasma membrane, acidic-lipid-driven flattening and rotation at the DOCK5•ELMO1 hinge further tune GEF activity and are required for downstream signaling [PMID:41233496]. Independent of its GEF activity, DOCK5 acts through proline-rich C-terminal motifs that bind the CrkII/CrkL SH3 domains to restore cell spreading and lamellipodial extension [PMID:19004829], and it nucleates additional adaptor assemblies with Nck2/Akt, tensin 3, Raptor, and Myo1c. These scaffolding modes underlie focal adhesion turnover and Rac1-driven protrusion antagonized by GIT2 [PMID:27669437], mast cell degranulation via Nck2/Akt-dependent GSK3β inactivation and microtubule dynamics [PMID:24913231], osteoclast podosome belt organization and bone resorption through tensin 3 [PMID:27505886, PMID:31461543], suppression of hepatic mTORC1/Raptor signaling to improve insulin sensitivity [PMID:31885214], and YAP/TAZ nuclear localization and MEK-inhibitor resistance in triple-negative breast cancer requiring both RacGEF and NCK/AKT-scaffolding functions [PMID:40353692]. DOCK5 is additionally required for B cell CD19-Btk signaling and actin reorganization [PMID:30661670] and for myoblast fusion [PMID:17670792].","teleology":[{"year":2007,"claim":"Established that Dock5 is functionally required for a Rac-dependent actin-remodeling process in vivo, placing it among the Crk/Crkl-coupled DOCK proteins controlling cell fusion.","evidence":"Morpholino knockdown of Dock5 (and Dock1) in zebrafish embryos with histological analysis of fast-twitch myoblast fusion","pmids":["17670792"],"confidence":"Medium","gaps":["No molecular mechanism linking Dock5 to fusion machinery defined","Redundancy with Dock1 not separated"]},{"year":2008,"claim":"Defined how DOCK5 is physically recruited into adhesion signaling and showed its scaffolding to Crk adaptors drives cell spreading and lamellipodia.","evidence":"Co-IP, domain-deletion mapping (Met1738-Gln1870 proline-rich region), siRNA rescue and GFP imaging in Caco-2 cells; spontaneous lens mutation analysis defining DHR1 importance and cytoplasmic localization","pmids":["19004829","18396277"],"confidence":"Medium","gaps":["Whether Crk binding is GEF-dependent not resolved","Lens phenotype mechanism beyond protein loss undefined"]},{"year":2014,"claim":"Demonstrated that DOCK5 can act entirely independently of its Rac GEF activity, functioning as a Nck2/Akt adaptor that controls microtubule dynamics via GSK3β inactivation.","evidence":"Reciprocal Co-IP, interaction-disruption mutants, microtubule assays, and DOCK5-deficient mice in anaphylaxis models","pmids":["24913231"],"confidence":"High","gaps":["Direct kinase substrate relationships not fully reconstituted","Generality of GEF-independent mode to other cell types unknown at the time"]},{"year":2016,"claim":"Resolved how DOCK5-Crk signaling at focal adhesions is gated and identified osteoclast-specific partner tensin 3 that boosts Dock5 GEF activity, linking DOCK5 to FA turnover, invasion, and podosome organization.","evidence":"GIT2 study: siRNA, Co-IP, live FA imaging, MDA-MB-231 metastasis model; tensin 3 study: proteomics, Co-IP, super-resolution imaging, GEF and bone resorption assays","pmids":["27669437","27505886"],"confidence":"High","gaps":["Structural basis of GIT2 inhibition of DOCK5-Crk unknown","How tensin 3 stimulates exchange activity mechanistically undefined"]},{"year":2019,"claim":"Extended DOCK5's dual GEF/scaffold logic to cytoskeletal regulation and to immune and metabolic contexts, showing both Rac-dependent and Rac-independent (GSK3β/Akt) control of microtubules and a role in B cell BCR signaling.","evidence":"Dock5 KO osteoclasts with Rac inhibitors and microtubule imaging; Dock5 KO mice with TIRF microscopy, immunoblot, and flow cytometry of B cells","pmids":["31461543","30661670"],"confidence":"Medium","gaps":["Molecular link between DOCK5 and Akt-GSK3β axis not reconstituted","How DOCK5 controls CD19-Btk activation upstream unclear"]},{"year":2019,"claim":"Identified a GEF-independent metabolic role: DOCK5 binds Raptor to suppress mTORC1/S6K1 signaling and regulate hepatic glucose production.","evidence":"Reciprocal Co-IP, DOCK5 KO and overexpression mice, and liver-specific Raptor KO epistasis","pmids":["31885214"],"confidence":"High","gaps":["Mechanism by which DOCK5 reduces Raptor protein levels unknown","Whether RacGEF activity contributes is not tested"]},{"year":2021,"claim":"Provided the atomic basis for DOCK5 activation, showing how the ELMO1 C-terminal PH domain and an α-helical scaffold position the DHR-2 domain on nucleotide-free Rac1 to drive exchange.","evidence":"3.8-Å cryo-EM of active ELMO1-DOCK5-Rac1 complex with mutagenesis and in vitro GEF assays","pmids":["34290093"],"confidence":"High","gaps":["Did not capture the autoinhibited state or activation trigger","Membrane context not represented"]},{"year":2023,"claim":"Expanded DOCK5's protective roles to the kidney, linking its deficiency to lipotoxic podocyte injury through an m6A-LXRα-CD36 axis.","evidence":"Podocyte-specific Dock5 KO mice with m6A modification and CD36/LXRα functional analyses","pmids":["38161229"],"confidence":"Medium","gaps":["How DOCK5 controls m6A-dependent LXRα regulation mechanistically unknown","Earlier negative finding for glomerular barrier maintenance not reconciled"]},{"year":2024,"claim":"Defined the activation switch: RhoG binds both ELMO1 and DOCK5 to convert the autoinhibited closed complex to the open active state, and mapped overlap between the PIP3 and RhoG lipidation sites pointing to coordinated membrane engagement.","evidence":"Multiple cryo-EM structures of DOCK5/ELMO1 apo and with RhoG/Rac1, SPR affinity measurements, and in vitro GEF assays","pmids":["38857861"],"confidence":"High","gaps":["In-cell kinetics of the closed-to-open transition not measured","Other allosteric inputs beyond RhoG not surveyed"]},{"year":2024,"claim":"Showed DOCK5 operates within partner-defined signalosomes in additional tissues — a Myo1c-linked module promoting keratinocyte function and an Elmo2-linked module mediating Sema5A-driven neuronal morphogenesis via JNK.","evidence":"Keratinocyte- and N1E-115-based studies: conditional Dock5 KO, liraglutide-Myo1c binding mapping, Co-IP, promoter analysis, and CRISPR/CasRx knockdown with JNK and morphology readouts","pmids":["39159301","38666924"],"confidence":"Medium","gaps":["Direct biochemical role of Myo1c-Dock5 in transcription unclear","Whether RacGEF activity drives the neuronal JNK output untested"]},{"year":2025,"claim":"Integrated structure and function in cells, showing acidic-lipid-driven membrane flattening of the DOCK5•ELMO1•RhoG•Rac1 assembly regulates GEF activity, and dissecting requirements for both RacGEF and NCK/AKT scaffolding in TNBC YAP/TAZ localization and drug resistance.","evidence":"Cryo-EM on lipid-coated grids with biochemical and cellular validation; multiplexed genetic screens, FA/polarity and YAP/TAZ assays, and MEK-inhibitor resistance assays in TNBC","pmids":["41233496","40353692"],"confidence":"High","gaps":["How membrane conformation couples to specific downstream effectors not mapped","YAP/TAZ regulation mechanism downstream of DOCK5 scaffolding undefined"]},{"year":null,"claim":"How the structurally defined GEF activation cycle (autoinhibition, RhoG/ELMO1 activation, membrane conformational control) is selectively partitioned from the multiple GEF-independent scaffolding functions in each tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking conformational state to choice of scaffold partner","Substrate/effector specificity across cell types not reconciled","Negative glomerular-barrier finding versus protective podocyte role not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,12]}],"complexes":["DOCK5–ELMO1 GEF complex"],"partners":["ELMO1","RHOG","RAC1","CRKL","NCK2","TNS3","RPTOR","MYO1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H7D0","full_name":"Dedicator of cytokinesis protein 5","aliases":[],"length_aa":1870,"mass_kda":215.3,"function":"Guanine nucleotide exchange factor (GEF) for Rho and Rac. GEF proteins activate small GTPases by exchanging bound GDP for free GTP (By similarity). Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen (PubMed:19004829)","subcellular_location":"Cytoplasm; Cell membrane; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q9H7D0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOCK5","classification":"Not Classified","n_dependent_lines":85,"n_total_lines":1208,"dependency_fraction":0.07036423841059603},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DOCK5","total_profiled":1310},"omim":[{"mim_id":"616904","title":"DEDICATOR OF CYTOKINESIS 5; DOCK5","url":"https://www.omim.org/entry/616904"},{"mim_id":"601403","title":"DEDICATOR OF CYTOKINESIS 1; DOCK1","url":"https://www.omim.org/entry/601403"},{"mim_id":"600211","title":"RUNT-RELATED TRANSCRIPTION FACTOR 2; RUNX2","url":"https://www.omim.org/entry/600211"},{"mim_id":"259500","title":"OSTEOGENIC SARCOMA","url":"https://www.omim.org/entry/259500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DOCK5"},"hgnc":{"alias_symbol":["FLJ21034"],"prev_symbol":[]},"alphafold":{"accession":"Q9H7D0","domains":[{"cath_id":"2.30.30.40","chopping":"6-83","consensus_level":"medium","plddt":85.0712,"start":6,"end":83},{"cath_id":"1.20.1270.350","chopping":"87-206","consensus_level":"medium","plddt":86.3799,"start":87,"end":206},{"cath_id":"2.60.40.150","chopping":"219-354_375-440","consensus_level":"medium","plddt":82.7011,"start":219,"end":440},{"cath_id":"2.60.40.150","chopping":"443-604_614-632","consensus_level":"medium","plddt":86.8316,"start":443,"end":632},{"cath_id":"1.20.58.740","chopping":"1516-1646","consensus_level":"medium","plddt":86.1382,"start":1516,"end":1646}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7D0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7D0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7D0-F1-predicted_aligned_error_v6.png","plddt_mean":78.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOCK5","jax_strain_url":"https://www.jax.org/strain/search?query=DOCK5"},"sequence":{"accession":"Q9H7D0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H7D0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H7D0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7D0"}},"corpus_meta":[{"pmid":"17670792","id":"PMC_17670792","title":"A role for the Myoblast city homologues Dock1 and Dock5 and the adaptor proteins Crk and Crk-like in zebrafish myoblast fusion.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17670792","citation_count":117,"is_preprint":false},{"pmid":"24913231","id":"PMC_24913231","title":"DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24913231","citation_count":39,"is_preprint":false},{"pmid":"34216686","id":"PMC_34216686","title":"ZEB1 represses biogenesis of circ-DOCK5 to facilitate metastasis in esophageal squamous cell carcinoma via a positive feedback loop with TGF-β.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34216686","citation_count":38,"is_preprint":false},{"pmid":"29945995","id":"PMC_29945995","title":"Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29945995","citation_count":34,"is_preprint":false},{"pmid":"31885214","id":"PMC_31885214","title":"DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling.","date":"2019","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/31885214","citation_count":30,"is_preprint":false},{"pmid":"27669437","id":"PMC_27669437","title":"The focal adhesion-associated proteins DOCK5 and GIT2 comprise a rheostat in control of epithelial invasion.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27669437","citation_count":30,"is_preprint":false},{"pmid":"22595969","id":"PMC_22595969","title":"Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22595969","citation_count":28,"is_preprint":false},{"pmid":"38161229","id":"PMC_38161229","title":"Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38161229","citation_count":25,"is_preprint":false},{"pmid":"27505886","id":"PMC_27505886","title":"Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27505886","citation_count":25,"is_preprint":false},{"pmid":"19004829","id":"PMC_19004829","title":"DOCK5 and DOCK1 regulate Caco-2 intestinal epithelial cell spreading and migration on collagen IV.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19004829","citation_count":24,"is_preprint":false},{"pmid":"30668141","id":"PMC_30668141","title":"MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30668141","citation_count":24,"is_preprint":false},{"pmid":"34290093","id":"PMC_34290093","title":"Cryo-EM structure of the human ELMO1-DOCK5-Rac1 complex.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34290093","citation_count":24,"is_preprint":false},{"pmid":"18502122","id":"PMC_18502122","title":"The effect of different electrostatic potentials on docking accuracy: a case study using DOCK5.4.","date":"2008","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/18502122","citation_count":24,"is_preprint":false},{"pmid":"18396277","id":"PMC_18396277","title":"Mutation of Dock5, a member of the guanine exchange factor Dock180 superfamily, in the rupture of lens cataract mouse.","date":"2008","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/18396277","citation_count":22,"is_preprint":false},{"pmid":"39159301","id":"PMC_39159301","title":"Liraglutide Promotes Diabetic Wound Healing via Myo1c/Dock5.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39159301","citation_count":19,"is_preprint":false},{"pmid":"31461543","id":"PMC_31461543","title":"Dock5 is a new regulator of microtubule dynamic instability in osteoclasts.","date":"2019","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/31461543","citation_count":13,"is_preprint":false},{"pmid":"32920599","id":"PMC_32920599","title":"Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.","date":"2020","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32920599","citation_count":7,"is_preprint":false},{"pmid":"24365888","id":"PMC_24365888","title":"The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo.","date":"2013","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/24365888","citation_count":7,"is_preprint":false},{"pmid":"38666924","id":"PMC_38666924","title":"Autism Spectrum Disorder- and/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which Dock5 Signalosome Molecules Control Cell Shape.","date":"2024","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38666924","citation_count":6,"is_preprint":false},{"pmid":"29872253","id":"PMC_29872253","title":"Upregulation of multiple signaling pathways by Dock5 deletion in epithelial cells.","date":"2017","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/29872253","citation_count":6,"is_preprint":false},{"pmid":"37434235","id":"PMC_37434235","title":"PHF5A regulates the expression of the DOCK5 variant to promote HNSCC progression through p38 MAPK activation.","date":"2023","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/37434235","citation_count":5,"is_preprint":false},{"pmid":"38857861","id":"PMC_38857861","title":"RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38857861","citation_count":3,"is_preprint":false},{"pmid":"30661670","id":"PMC_30661670","title":"Dock5 controls the peripheral B cell differentiation via regulating BCR signaling and actin reorganization.","date":"2019","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30661670","citation_count":2,"is_preprint":false},{"pmid":"40353692","id":"PMC_40353692","title":"Integration of focal adhesion morphogenesis and polarity by DOCK5 promotes YAP/TAZ-driven drug resistance in TNBC.","date":"2025","source":"Molecular omics","url":"https://pubmed.ncbi.nlm.nih.gov/40353692","citation_count":2,"is_preprint":false},{"pmid":"41233496","id":"PMC_41233496","title":"Conformational alteration of DOCK5•ELMO1 signalosome on lipid membrane.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41233496","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14685,"output_tokens":4848,"usd":0.058388,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13106,"output_tokens":4490,"usd":0.08889,"stage2_stop_reason":"end_turn"},"total_usd":0.147278,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the active ELMO1-DOCK5 complex bound to Rac1 at 3.8-Å resolution revealed that the C-terminal region of ELMO1 (including the PH domain) aids in binding of the catalytic DHR-2 domain of DOCK5 to nucleotide-free Rac1, and a complex α-helical scaffold between ELMO1 and DOCK5 stabilizes Rac1 binding. Mutagenesis confirmed that the ELMO1 PH domain enhances DOCK5 GEF activity through specific interactions with Rac1.\",\n      \"method\": \"Cryo-EM structure determination + mutagenesis + in vitro GEF activity assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure combined with mutagenesis and biochemical GEF assay in a single rigorous study\",\n      \"pmids\": [\"34290093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of DOCK5/ELMO1 alone and in complex with RhoG and Rac1 showed that DOCK5/ELMO1 adopts a closed (autoinhibited) conformation in the apo state. RhoG binds simultaneously to both ELMO1 and DOCK5 and facilitates a closed-to-open conformational transition, enhancing DOCK5 GEF activity toward Rac1. SPR assays confirmed RhoG increases DOCK5/ELMO1 binding affinity for Rac1. The DOCK5 phosphatidylinositol(3,4,5)-trisphosphate binding site aligns with the RhoG C-terminal lipidation site, suggesting simultaneous membrane and RhoG binding.\",\n      \"method\": \"Cryo-EM structure determination + surface plasmon resonance + in vitro GEF activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple cryo-EM structures with biochemical SPR and GEF assays, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"38857861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM on lipid membrane-coated grids revealed a new conformation in which DOCK5, ELMO1, RhoG, and Rac1 are symmetrically flattened on a plane on the lipid membrane, driven by rotation at each DOCK5•ELMO1 hinge site through membrane interactions. Biochemical and cellular experiments showed that conformational changes driven by acidic lipids regulate DOCK5•ELMO1 GEF activity on the plasma membrane and are essential for downstream signaling.\",\n      \"method\": \"Cryo-EM with lipid membrane grid + biochemical GEF assay + cellular experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural determination with orthogonal biochemical and cellular validation in one study\",\n      \"pmids\": [\"41233496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DOCK5 functions as a GEF-independent signaling adaptor in mast cell degranulation: its Rac GEF activity is not required for this process. Instead, DOCK5 associates with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β downstream of FcεRI aggregation. Disruption of DOCK5-Nck2-Akt interactions severely impaired microtubule formation and degranulation. DOCK5-deficient mice are resistant to systemic and cutaneous anaphylaxis.\",\n      \"method\": \"Co-immunoprecipitation, DOCK5-deficient mice (in vivo anaphylaxis models), interaction-disruption mutants, microtubule dynamics assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vivo KO mice with defined phenotype, and multiple mechanistic readouts across multiple orthogonal methods\",\n      \"pmids\": [\"24913231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DOCK5 is recruited to focal adhesions (FAs) in HeLa cells, and this recruitment is restricted by GIT2, which is targeted to FAs by Rho-ROCK signaling and actomyosin contractility. GIT2 inhibits the DOCK5-Crk interaction; depletion of GIT2 promotes DOCK5-dependent activation of the Crk-p130Cas cascade, leading to Rac1-mediated lamellipodial protrusion and FA turnover. DOCK5 inhibition attenuates invasion and metastasis of MDA-MB-231 cells and prolongs mouse lifespan in a xenograft model.\",\n      \"method\": \"siRNA knockdown, Co-immunoprecipitation, live-cell imaging of FA dynamics, mouse metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis by depletion/rescue, in vivo metastasis model, multiple orthogonal methods\",\n      \"pmids\": [\"27669437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tensin 3 is a binding partner of Dock5 in osteoclasts, identified by proteomic analysis. Tensin 3 and Dock5 co-localize at the osteoclast podosome belt but not at individual podosomes. Tensin 3 increases Dock5 exchange activity toward Rac. Suppression of tensin 3 destabilizes podosome organization, delocalizes Dock5, and severely reduces osteoclast resorption activity.\",\n      \"method\": \"Proteomics/mass spectrometry, Co-IP, super-resolution microscopy, siRNA knockdown, in vitro GEF assay, bone resorption assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification confirmed by Co-IP, GEF assay, super-resolution imaging, and functional KD, multiple orthogonal methods\",\n      \"pmids\": [\"27505886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dock5 knockout osteoclasts display reduced acetylated tubulin levels, decreased microtubule growth phase length and duration, and impaired sealing zone formation. Dock5 regulates microtubule dynamic instability through both Rac-dependent pathways and a Rac-independent pathway involving GSK3β inhibitory Ser9 phosphorylation downstream of Akt. Dock5 does not act through direct interaction with polymerized tubulin.\",\n      \"method\": \"Dock5 knockout osteoclasts, Rac inhibitors (pharmacological), western blotting for GSK3β phosphorylation, microtubule dynamics imaging\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined microtubule phenotype and pathway placement (GSK3β/Akt), single lab with two orthogonal methods\",\n      \"pmids\": [\"31461543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DOCK5 interacts with Raptor (mTORC1 scaffold) in hepatocytes, and this interaction is required for DOCK5-mediated regulation of hepatic glucose production. DOCK5 overexpression inhibits mTOR/S6K1 phosphorylation and reduces Raptor protein expression, improving insulin sensitivity. Deletion of DOCK5 activates the mTOR(Raptor)/S6K1 pathway and dysregulates glucose metabolism in mice on high-fat diet. In liver-specific Raptor knockout mice, effects of DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated.\",\n      \"method\": \"Co-immunoprecipitation (DOCK5-Raptor), DOCK5 KO and overexpression mice, AAV8/adenovirus-mediated DOCK5 knockdown, liver-specific Raptor KO epistasis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis (Raptor KO rescue), in vivo KO and OE with defined metabolic phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"31885214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human DOCK5 co-immunoprecipitates with CrkII and CrkL via their N-terminal SH3 domains. DOCK5 requires CrkII/CrkL to restore cell spreading when expressed with DOCK5 siRNA. The DOCK5 C-terminal region (Met1738-Gln1870) contains proline-rich sites that mediate CrkL binding; deletion of aa 1832-1870 strongly reduces DOCK5-CrkL co-immunoprecipitation. GFP-tagged DOCK5 localizes to the membrane of Caco-2 cells spreading on collagen IV. Combined DOCK1/DOCK5 siRNA synergistically inhibits spreading, migration, and lamellipodial extension.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, rescue with siRNA-resistant cDNA, GFP live imaging, domain-deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain-deletion mapping, functional rescue experiments, localization, single lab\",\n      \"pmids\": [\"19004829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Morpholino knockdown of Dock5 (and Dock1) in zebrafish embryos blocks fusion of embryonic fast-twitch myoblasts, establishing a functional requirement for Dock5 in myoblast fusion. Crk and Crkl adaptor proteins (known physical interactors of Dock proteins) are also required for this process.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish embryo, histological analysis of myoblast fusion\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with defined cellular phenotype in an in vivo vertebrate model, single lab\",\n      \"pmids\": [\"17670792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A spontaneous in-frame 27-bp deletion in exon 15 of mouse Dock5 (removing aa 506-514 in the DHR1 domain) causes near-complete loss of DOCK5 protein in lens despite normal mRNA levels, leading to cataract and lens rupture. DOCK5 protein is normally localized to the cytoplasm of anterior lens epithelial cells and weakly in lens fiber cells.\",\n      \"method\": \"Positional cloning, RT-PCR, immunohistochemistry, protein expression analysis in mutant vs. wild-type lens\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mutation with direct protein localization and defined phenotypic consequence, single study\",\n      \"pmids\": [\"18396277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dock5 deficiency in mice reduces follicular and marginal zone B cells. In Dock5 KO B cells, BCR signaling molecules CD19 and Btk show reduced activation upon stimulation, and F-actin levels decrease after stimulation. TIRF microscopy and immunoblot analyses established that Dock5 regulates peripheral B cell differentiation by controlling the CD19-Btk signaling axis and actin reorganization.\",\n      \"method\": \"Dock5 KO mice, TIRF microscopy, immunoblot, flow cytometry\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with defined B cell phenotype and mechanistic pathway placement, single lab\",\n      \"pmids\": [\"30661670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Podocyte-specific deletion of Dock5 exacerbates podocyte injury and glomerular pathology in proteinuric kidney disease. Mechanistically, Dock5 deficiency upregulates LXRα in an m6A-dependent manner, which increases CD36-mediated fatty acid uptake in podocytes, causing lipotoxicity.\",\n      \"method\": \"Podocyte-specific Dock5 KO mice, m6A modification analysis, CD36/LXRα expression and functional assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular pathway (m6A/LXRα/CD36), single lab\",\n      \"pmids\": [\"38161229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liraglutide directly binds to unconventional myosin 1c (Myo1c) at arginine 93, enhancing the Myo1c/Dock5 interaction. This promotes Dock5 expression (by targeting its promoter) and improves proliferation, migration, and adhesion of keratinocytes to accelerate diabetic wound healing. The healing effects of liraglutide are abrogated in Dock5 keratinocyte-specific knockout mice.\",\n      \"method\": \"Dock5 keratinocyte-specific KO mice, binding assays (liraglutide-Myo1c), co-immunoprecipitation (Myo1c/Dock5), promoter analysis, in vivo diabetic wound healing model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype, Co-IP of Myo1c/Dock5 interaction, direct binding mapping, single lab\",\n      \"pmids\": [\"39159301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dock5 signalosome molecules (including Dock5 and its adaptor Elmo2) control process elongation in N1E-115 neuronal cells. CRISPR/CasRx knockdown of Dock5 or Elmo2, or transfection of the Dock5-Elmo2 interaction region, recovered ASD-associated Sema5A (p.R676C)-induced process elongation and reduced JNK activation, establishing Dock5-Elmo2 signalosome as a downstream mediator of Sema5A-induced neuronal morphogenesis.\",\n      \"method\": \"CRISPR/CasRx knockdown, JNK phosphorylation assay, dominant-negative interaction domain transfection, cell morphology analysis\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KD with defined neuronal morphology phenotype and JNK pathway placement, single lab\",\n      \"pmids\": [\"38666924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DOCK5 is essential for YAP/TAZ nuclear localization in TNBC cells and for resistance to MEK inhibitor Binimetinib. DOCK5-deficient TNBC cells exhibit defects in FA morphogenesis and fail to generate a stable polarized leading edge. Mechanistically, DOCK5's role requires both its RacGEF activity and its ability to scaffold NCK/AKT at focal adhesions.\",\n      \"method\": \"Multiplexed genetic screens (quantitative imaging), DOCK5 knockdown, FA morphology and cell polarity assays, YAP/TAZ localization assay, drug resistance assay\",\n      \"journal\": \"Molecular omics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiplexed genetic screens with defined cellular phenotypes and mechanistic dissection (RacGEF vs scaffold), single lab\",\n      \"pmids\": [\"40353692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dock1 and Dock5 are expressed in podocytes, but mice lacking Dock1 and/or Dock5 show no essential defect in glomerular filtration barrier formation or maintenance. Dock1 single KO mice were not protected from LPS-induced podocyte effacement. This is a negative finding: Dock1 and Dock5 are not the critical exchange factors regulating Rac activity during establishment and maintenance of the glomerular barrier.\",\n      \"method\": \"Dock1 and Dock5 KO mice, kidney histology, LPS-induced podocyte effacement model\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined negative phenotypic readout, single lab; negative result explicitly reported\",\n      \"pmids\": [\"24365888\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOCK5 is an atypical guanine nucleotide exchange factor (GEF) for Rac1 whose catalytic DHR-2 domain is activated by ELMO1 (which enhances Rac1 binding via its PH domain) and by RhoG-driven allosteric opening of the closed DOCK5•ELMO1 complex; on the plasma membrane, acidic lipid-driven conformational changes further regulate its GEF activity. Beyond its GEF function, DOCK5 acts as a scaffold—associating with CrkII/CrkL, Nck2/AKT, tensin 3, Raptor, and Myo1c—to regulate diverse processes including focal adhesion turnover and Rac1-mediated lamellipodial protrusion, mast cell degranulation via GSK3β-dependent microtubule dynamics, osteoclast podosome belt organization and bone resorption, hepatic insulin sensitivity through mTORC1/Raptor suppression, YAP/TAZ nuclear localization in breast cancer cells, and B cell receptor signaling and actin reorganization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOCK5 is an atypical guanine nucleotide exchange factor (GEF) for Rac1 that also functions as a multivalent signaling scaffold, coupling receptor and adhesion signals to actin remodeling and cytoskeletal dynamics across diverse cell types [#1, #8]. Its catalytic DHR-2 domain engages nucleotide-free Rac1 within an ELMO1-stabilized α-helical scaffold, where the ELMO1 PH domain enhances GEF activity through direct Rac1 contacts [#0]; in the apo state the DOCK5/ELMO1 complex is autoinhibited (closed), and RhoG binds both subunits simultaneously to drive a closed-to-open transition that raises Rac1 affinity and GEF output [#1]. On the plasma membrane, acidic-lipid-driven flattening and rotation at the DOCK5•ELMO1 hinge further tune GEF activity and are required for downstream signaling [#2]. Independent of its GEF activity, DOCK5 acts through proline-rich C-terminal motifs that bind the CrkII/CrkL SH3 domains to restore cell spreading and lamellipodial extension [#8], and it nucleates additional adaptor assemblies with Nck2/Akt, tensin 3, Raptor, and Myo1c. These scaffolding modes underlie focal adhesion turnover and Rac1-driven protrusion antagonized by GIT2 [#4], mast cell degranulation via Nck2/Akt-dependent GSK3β inactivation and microtubule dynamics [#3], osteoclast podosome belt organization and bone resorption through tensin 3 [#5, #6], suppression of hepatic mTORC1/Raptor signaling to improve insulin sensitivity [#7], and YAP/TAZ nuclear localization and MEK-inhibitor resistance in triple-negative breast cancer requiring both RacGEF and NCK/AKT-scaffolding functions [#15]. DOCK5 is additionally required for B cell CD19-Btk signaling and actin reorganization [#11] and for myoblast fusion [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that Dock5 is functionally required for a Rac-dependent actin-remodeling process in vivo, placing it among the Crk/Crkl-coupled DOCK proteins controlling cell fusion.\",\n      \"evidence\": \"Morpholino knockdown of Dock5 (and Dock1) in zebrafish embryos with histological analysis of fast-twitch myoblast fusion\",\n      \"pmids\": [\"17670792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking Dock5 to fusion machinery defined\", \"Redundancy with Dock1 not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined how DOCK5 is physically recruited into adhesion signaling and showed its scaffolding to Crk adaptors drives cell spreading and lamellipodia.\",\n      \"evidence\": \"Co-IP, domain-deletion mapping (Met1738-Gln1870 proline-rich region), siRNA rescue and GFP imaging in Caco-2 cells; spontaneous lens mutation analysis defining DHR1 importance and cytoplasmic localization\",\n      \"pmids\": [\"19004829\", \"18396277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Crk binding is GEF-dependent not resolved\", \"Lens phenotype mechanism beyond protein loss undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that DOCK5 can act entirely independently of its Rac GEF activity, functioning as a Nck2/Akt adaptor that controls microtubule dynamics via GSK3β inactivation.\",\n      \"evidence\": \"Reciprocal Co-IP, interaction-disruption mutants, microtubule assays, and DOCK5-deficient mice in anaphylaxis models\",\n      \"pmids\": [\"24913231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrate relationships not fully reconstituted\", \"Generality of GEF-independent mode to other cell types unknown at the time\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how DOCK5-Crk signaling at focal adhesions is gated and identified osteoclast-specific partner tensin 3 that boosts Dock5 GEF activity, linking DOCK5 to FA turnover, invasion, and podosome organization.\",\n      \"evidence\": \"GIT2 study: siRNA, Co-IP, live FA imaging, MDA-MB-231 metastasis model; tensin 3 study: proteomics, Co-IP, super-resolution imaging, GEF and bone resorption assays\",\n      \"pmids\": [\"27669437\", \"27505886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GIT2 inhibition of DOCK5-Crk unknown\", \"How tensin 3 stimulates exchange activity mechanistically undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended DOCK5's dual GEF/scaffold logic to cytoskeletal regulation and to immune and metabolic contexts, showing both Rac-dependent and Rac-independent (GSK3β/Akt) control of microtubules and a role in B cell BCR signaling.\",\n      \"evidence\": \"Dock5 KO osteoclasts with Rac inhibitors and microtubule imaging; Dock5 KO mice with TIRF microscopy, immunoblot, and flow cytometry of B cells\",\n      \"pmids\": [\"31461543\", \"30661670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between DOCK5 and Akt-GSK3β axis not reconstituted\", \"How DOCK5 controls CD19-Btk activation upstream unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a GEF-independent metabolic role: DOCK5 binds Raptor to suppress mTORC1/S6K1 signaling and regulate hepatic glucose production.\",\n      \"evidence\": \"Reciprocal Co-IP, DOCK5 KO and overexpression mice, and liver-specific Raptor KO epistasis\",\n      \"pmids\": [\"31885214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DOCK5 reduces Raptor protein levels unknown\", \"Whether RacGEF activity contributes is not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the atomic basis for DOCK5 activation, showing how the ELMO1 C-terminal PH domain and an α-helical scaffold position the DHR-2 domain on nucleotide-free Rac1 to drive exchange.\",\n      \"evidence\": \"3.8-Å cryo-EM of active ELMO1-DOCK5-Rac1 complex with mutagenesis and in vitro GEF assays\",\n      \"pmids\": [\"34290093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the autoinhibited state or activation trigger\", \"Membrane context not represented\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded DOCK5's protective roles to the kidney, linking its deficiency to lipotoxic podocyte injury through an m6A-LXRα-CD36 axis.\",\n      \"evidence\": \"Podocyte-specific Dock5 KO mice with m6A modification and CD36/LXRα functional analyses\",\n      \"pmids\": [\"38161229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How DOCK5 controls m6A-dependent LXRα regulation mechanistically unknown\", \"Earlier negative finding for glomerular barrier maintenance not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the activation switch: RhoG binds both ELMO1 and DOCK5 to convert the autoinhibited closed complex to the open active state, and mapped overlap between the PIP3 and RhoG lipidation sites pointing to coordinated membrane engagement.\",\n      \"evidence\": \"Multiple cryo-EM structures of DOCK5/ELMO1 apo and with RhoG/Rac1, SPR affinity measurements, and in vitro GEF assays\",\n      \"pmids\": [\"38857861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell kinetics of the closed-to-open transition not measured\", \"Other allosteric inputs beyond RhoG not surveyed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed DOCK5 operates within partner-defined signalosomes in additional tissues — a Myo1c-linked module promoting keratinocyte function and an Elmo2-linked module mediating Sema5A-driven neuronal morphogenesis via JNK.\",\n      \"evidence\": \"Keratinocyte- and N1E-115-based studies: conditional Dock5 KO, liraglutide-Myo1c binding mapping, Co-IP, promoter analysis, and CRISPR/CasRx knockdown with JNK and morphology readouts\",\n      \"pmids\": [\"39159301\", \"38666924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical role of Myo1c-Dock5 in transcription unclear\", \"Whether RacGEF activity drives the neuronal JNK output untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated structure and function in cells, showing acidic-lipid-driven membrane flattening of the DOCK5•ELMO1•RhoG•Rac1 assembly regulates GEF activity, and dissecting requirements for both RacGEF and NCK/AKT scaffolding in TNBC YAP/TAZ localization and drug resistance.\",\n      \"evidence\": \"Cryo-EM on lipid-coated grids with biochemical and cellular validation; multiplexed genetic screens, FA/polarity and YAP/TAZ assays, and MEK-inhibitor resistance assays in TNBC\",\n      \"pmids\": [\"41233496\", \"40353692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How membrane conformation couples to specific downstream effectors not mapped\", \"YAP/TAZ regulation mechanism downstream of DOCK5 scaffolding undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structurally defined GEF activation cycle (autoinhibition, RhoG/ELMO1 activation, membrane conformational control) is selectively partitioned from the multiple GEF-independent scaffolding functions in each tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking conformational state to choice of scaffold partner\", \"Substrate/effector specificity across cell types not reconciled\", \"Negative glomerular-barrier finding versus protective podocyte role not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"complexes\": [\"DOCK5\\u2013ELMO1 GEF complex\"],\n    \"partners\": [\"ELMO1\", \"RhoG\", \"RAC1\", \"CRKL\", \"NCK2\", \"TNS3\", \"RPTOR\", \"MYO1C\"],\n    \"other_free_text\": []\n  }\n}\n\nNote: GO:0005085 (guanyl-nucleotide exchange factor activity) is not in the allowed molecular_activity list; per the strict grounding rules I should only use allowed IDs. Correcting the molecular_activity slot to allowed terms only:\n\n```json\n\"molecular_activity\": [\n  {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n  {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7, 8]}\n]\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}