Affinage

DOCK5

Dedicator of cytokinesis protein 5 · UniProt Q9H7D0

Length
1870 aa
Mass
215.3 kDa
Annotated
2026-06-09
25 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2007 Medium

    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

    PMID:17670792

    Open questions at the time
    • No molecular mechanism linking Dock5 to fusion machinery defined
    • Redundancy with Dock1 not separated
  2. 2008 Medium

    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

    PMID:18396277 PMID:19004829

    Open questions at the time
    • Whether Crk binding is GEF-dependent not resolved
    • Lens phenotype mechanism beyond protein loss undefined
  3. 2014 High

    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

    PMID:24913231

    Open questions at the time
    • Direct kinase substrate relationships not fully reconstituted
    • Generality of GEF-independent mode to other cell types unknown at the time
  4. 2016 High

    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

    PMID:27505886 PMID:27669437

    Open questions at the time
    • Structural basis of GIT2 inhibition of DOCK5-Crk unknown
    • How tensin 3 stimulates exchange activity mechanistically undefined
  5. 2019 Medium

    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

    PMID:30661670 PMID:31461543

    Open questions at the time
    • Molecular link between DOCK5 and Akt-GSK3β axis not reconstituted
    • How DOCK5 controls CD19-Btk activation upstream unclear
  6. 2019 High

    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

    PMID:31885214

    Open questions at the time
    • Mechanism by which DOCK5 reduces Raptor protein levels unknown
    • Whether RacGEF activity contributes is not tested
  7. 2021 High

    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

    PMID:34290093

    Open questions at the time
    • Did not capture the autoinhibited state or activation trigger
    • Membrane context not represented
  8. 2023 Medium

    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

    PMID:38161229

    Open questions at the time
    • How DOCK5 controls m6A-dependent LXRα regulation mechanistically unknown
    • Earlier negative finding for glomerular barrier maintenance not reconciled
  9. 2024 High

    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

    PMID:38857861

    Open questions at the time
    • In-cell kinetics of the closed-to-open transition not measured
    • Other allosteric inputs beyond RhoG not surveyed
  10. 2024 Medium

    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

    PMID:38666924 PMID:39159301

    Open questions at the time
    • Direct biochemical role of Myo1c-Dock5 in transcription unclear
    • Whether RacGEF activity drives the neuronal JNK output untested
  11. 2025 High

    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

    PMID:40353692 PMID:41233496

    Open questions at the time
    • How membrane conformation couples to specific downstream effectors not mapped
    • YAP/TAZ regulation mechanism downstream of DOCK5 scaffolding undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2
Partners
CRKLELMO1MYO1CNCK2RAC1RHOGRPTORTNS3
Complex memberships
DOCK5–ELMO1 GEF complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. Cryo-EM structure determination + mutagenesis + in vitro GEF activity assay Science advances High 34290093
2024 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. Cryo-EM structure determination + surface plasmon resonance + in vitro GEF activity assay The Journal of biological chemistry High 38857861
2025 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. Cryo-EM with lipid membrane grid + biochemical GEF assay + cellular experiments Communications biology High 41233496
2014 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. Co-immunoprecipitation, DOCK5-deficient mice (in vivo anaphylaxis models), interaction-disruption mutants, microtubule dynamics assay The Journal of experimental medicine High 24913231
2016 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. siRNA knockdown, Co-immunoprecipitation, live-cell imaging of FA dynamics, mouse metastasis model Oncogene High 27669437
2016 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. Proteomics/mass spectrometry, Co-IP, super-resolution microscopy, siRNA knockdown, in vitro GEF assay, bone resorption assay Journal of cell science High 27505886
2019 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. Dock5 knockout osteoclasts, Rac inhibitors (pharmacological), western blotting for GSK3β phosphorylation, microtubule dynamics imaging Biology of the cell Medium 31461543
2019 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. Co-immunoprecipitation (DOCK5-Raptor), DOCK5 KO and overexpression mice, AAV8/adenovirus-mediated DOCK5 knockdown, liver-specific Raptor KO epistasis EMBO reports High 31885214
2008 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. Co-immunoprecipitation, siRNA knockdown, rescue with siRNA-resistant cDNA, GFP live imaging, domain-deletion mutants The Journal of biological chemistry Medium 19004829
2007 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. Morpholino antisense knockdown in zebrafish embryo, histological analysis of myoblast fusion Development (Cambridge, England) Medium 17670792
2008 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. Positional cloning, RT-PCR, immunohistochemistry, protein expression analysis in mutant vs. wild-type lens Experimental eye research Medium 18396277
2019 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. Dock5 KO mice, TIRF microscopy, immunoblot, flow cytometry Cellular immunology Medium 30661670
2023 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. Podocyte-specific Dock5 KO mice, m6A modification analysis, CD36/LXRα expression and functional assays Advanced science Medium 38161229
2024 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. Dock5 keratinocyte-specific KO mice, binding assays (liraglutide-Myo1c), co-immunoprecipitation (Myo1c/Dock5), promoter analysis, in vivo diabetic wound healing model Advanced science Medium 39159301
2024 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. CRISPR/CasRx knockdown, JNK phosphorylation assay, dominant-negative interaction domain transfection, cell morphology analysis Current issues in molecular biology Medium 38666924
2025 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. Multiplexed genetic screens (quantitative imaging), DOCK5 knockdown, FA morphology and cell polarity assays, YAP/TAZ localization assay, drug resistance assay Molecular omics Medium 40353692
2013 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. Dock1 and Dock5 KO mice, kidney histology, LPS-induced podocyte effacement model Small GTPases Medium 24365888

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 A role for the Myoblast city homologues Dock1 and Dock5 and the adaptor proteins Crk and Crk-like in zebrafish myoblast fusion. Development (Cambridge, England) 117 17670792
2014 DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation. The Journal of experimental medicine 39 24913231
2021 ZEB1 represses biogenesis of circ-DOCK5 to facilitate metastasis in esophageal squamous cell carcinoma via a positive feedback loop with TGF-β. Cancer letters 38 34216686
2018 Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant. Clinical cancer research : an official journal of the American Association for Cancer Research 34 29945995
2019 DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling. EMBO reports 30 31885214
2016 The focal adhesion-associated proteins DOCK5 and GIT2 comprise a rheostat in control of epithelial invasion. Oncogene 30 27669437
2012 Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity. Human molecular genetics 28 22595969
2023 Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 38161229
2016 Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity. Journal of cell science 25 27505886
2021 Cryo-EM structure of the human ELMO1-DOCK5-Rac1 complex. Science advances 24 34290093
2019 MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 30668141
2008 The effect of different electrostatic potentials on docking accuracy: a case study using DOCK5.4. Bioorganic & medicinal chemistry letters 24 18502122
2008 DOCK5 and DOCK1 regulate Caco-2 intestinal epithelial cell spreading and migration on collagen IV. The Journal of biological chemistry 24 19004829
2008 Mutation of Dock5, a member of the guanine exchange factor Dock180 superfamily, in the rupture of lens cataract mouse. Experimental eye research 22 18396277
2024 Liraglutide Promotes Diabetic Wound Healing via Myo1c/Dock5. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 39159301
2019 Dock5 is a new regulator of microtubule dynamic instability in osteoclasts. Biology of the cell 13 31461543
2020 Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation. Journal of human genetics 7 32920599
2013 The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo. Small GTPases 7 24365888
2024 Autism Spectrum Disorder- and/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which Dock5 Signalosome Molecules Control Cell Shape. Current issues in molecular biology 6 38666924
2017 Upregulation of multiple signaling pathways by Dock5 deletion in epithelial cells. Molecular vision 6 29872253
2023 PHF5A regulates the expression of the DOCK5 variant to promote HNSCC progression through p38 MAPK activation. Biology direct 5 37434235
2024 RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state. The Journal of biological chemistry 3 38857861
2025 Integration of focal adhesion morphogenesis and polarity by DOCK5 promotes YAP/TAZ-driven drug resistance in TNBC. Molecular omics 2 40353692
2019 Dock5 controls the peripheral B cell differentiation via regulating BCR signaling and actin reorganization. Cellular immunology 2 30661670
2025 Conformational alteration of DOCK5•ELMO1 signalosome on lipid membrane. Communications biology 0 41233496

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