DOCK6 is a DOCK-family guanine-nucleotide exchange factor that activates Rac1 and CDC42 signaling and helps regulate actin organization and cell morphology. It occupies cytosolic and perinuclear pools, and association with LRCH proteins can redistribute it toward the cell periphery. DOCK6-dependent signaling contributes to neuronal outgrowth, while biallelic human DOCK6 disruption causes Adams–Oliver syndrome with vascular and limb abnormalities. Its signaling output is sensitive to cellular regulatory context.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Reason: DOCK6 is a DOCK-family guanine-nucleotide exchange factor. Its exact 2047-residue sequence matches the PAINT target leaf, which descends from the experimentally grounded Eukaryota node PTN000593987. Current donor records include direct GEF annotations and fly genetic evidence. The DOCK6 study reports Rac1/CDC42 exchange and mouse N1E-115 responses, although its complete Methods and introduced-construct species could not be checked. A later human-cell FRET screen was negative under its assay conditions; this does not establish loss of the inherited activity or invalidate the ancestral placement. The current GEF term has no more specific is_a child for these substrates. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000593987 SUPPORTS TRANSFER Literal IBD, 21-node target descent and exact MSA sequence were reconstructed; experimentally grounded donors support inheritance, without donor-count or self-source criticism. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000002 | ACCEPT | Reason: The official IPR026791 DOCK-family record maps to guanyl-nucleotide exchange factor activity, and DOCK6 has that family assignment and target-specific GEF evidence. The mapping is supported without transferring DOCK1-specific ELMO or SH3 interactions to DOCK6. Negative activation in the 2020 human-cell screen is assay-specific and does not outweigh the positive Dock6 exchange evidence or justify calling this protein inactive. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR026791 SUPPORTS TRANSFER Actual family entry and target membership support the GEF mapping. |
| GO:0005515 protein binding | IPI PMID:32203420 Systems analysis of RhoGEF and RhoGAP regulatory proteins re... | KEEP AS NON CORE | Reason: The supporting partner O75427 is LRCH4. Two exact DOCK6–LRCH4 records join this publication: an AP-MS association and a targeted FLAG-LRCH4/mCherry-DOCK6 co-immunoprecipitation in HEK293T cells. Both sequence/taxon identifiers match the current human proteins, and the library DNA encodes the current 2047-residue DOCK6 sequence. The original Figure 6f and supplementary Table 3 support the association; the interaction database labels the targeted panel 6E. These experiments do not measure purified binary affinity or establish a distinct DOCK6 adaptor activity. Retain this positive generic association as non-core under the project instruction. Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Reason: The broad cytoplasmic annotation is supported. Refine it to the complementary cytosolic and perinuclear pools: target-resolved HPA ICC/IF and the human DOCK6 localization study support cytosol, while the curated UniProt record explicitly attributes perinuclear localization to experimental evidence from PMID:17196961. Both terms are descendants of cytoplasm, and neither is an ancestor of the other. These are nonexclusive pools, not mutually exclusive cell states. The original 2007 localization Methods remain unavailable, so its exact cell and construct context is not independently established. The cell-peripheral distribution reported in UniProt and with LRCH coexpression is retained descriptively without assigning a membrane or cortex term from proximity alone. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER The SL-0086 mapping is valid. Target cytosol evidence and the curated ECO:0000269 perinuclear assertion support complementary, nonexclusive refinements; proximity to the cell surface does not establish a named membrane compartment. Proposed replacements: cytosol perinuclear region of cytoplasm |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Reason: The exact DOCK6 PAINT leaf descends from PTN002762118, where the literal cytosol IBD includes Q96HP0 as an experimental descendant. The target appearing among its own supporting descendants is legitimate grounding, not circular evidence. The current HPA target record and human DOCK6 localization experiment independently support cytosol. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002762118 SUPPORTS TRANSFER Literal Euteleostomi-node IBD and target descent are verified; the Q96HP0 source is supported by target immunofluorescence. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Reason: The HPA record resolves DOCK6 to ENSG00000130158 and Q96HP0 and reports a supported ICC/IF main localization in cytosol. The data record was inspected directly; no independent interpretation of the microscopy pixels is claimed. This supports a cytosolic pool without excluding regulated peripheral redistribution. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1011598 | ACCEPT | Reason: The Reactome event contains DOCK-GEF set R-HSA-1012978, whose explicit member R-HSA-1012966 is human Q96HP0 residues 1–2047 in cytosol. Thus the location applies to DOCK6 itself, not merely another set member. This modeled pool is independently corroborated by HPA and the localization study. The event title calls the binding partners RhoGEFs, whereas its description and substrate set concern Rho GTPases; the location assessment does not depend on that title wording. |
| GO:0007264 small GTPase-mediated signal transduction | IEA GO_REF:0000002 | MODIFY | Reason: DOCK6 acts on Rho-family small GTPases, so Rho protein signal transduction is a supported refinement of the broad small-GTPase process. The current ontology places GO:0007266 beneath GO:0007264 through is_a/part_of ancestry. Nucleotide exchange is the performed molecular step; this decision does not derive participation from developmental or disease necessity. Rac1/CDC42 activation is reported in the Dock6 studies, with the negative 2020 human FRET screen retained as a conditional assay result. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR026791 SUPPORTS TRANSFER The family-to-process mapping is biologically supported; Rho-family substrate specificity supplies a narrower process. Proposed replacements: Rho protein signal transduction |
| GO:0035023 regulation of Rho protein signal transduction | IBA GO_REF:0000033 | MODIFY | Reason: The inherited regulatory role is supported: DOCK6 descends from the literal PTN000593987 IBD, and its fly Zir donor has experimental genetic interactions with Rac2 and Cdc42 in PMID:22634526. Target Dock6 exchange and activation evidence supports the positive direction, allowing refinement to positive regulation of Rho protein signal transduction. The current typed ancestry confirms this is a child of the imported regulation term. This sign comes from the GEF-mediated activation step, not from patient morphology or neuronal necessity. The exact full Methods of the 2007 and 2013 studies remain unavailable, and the 2020 negative activation screen does not establish universal inactivity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000593987 SUPPORTS TRANSFER Literal node placement and fly experimental grounding are supported; positive direction is supplied by target GEF evidence. Proposed replacements: positive regulation of Rho protein signal transduction Supporting Evidence: GO_REF:0000033 PMID:17196961 reduces activation of Rac1 and Cdc42 and neurite outgrowth. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Reason: Retain the positive perinuclear observation by deferring to the curated UniProt record, which explicitly attaches ECO:0000269 and PMID:17196961 to this location. The SL-0198 mapping is appropriate. The previous uncertainty gave excessive weight to unavailable original localization Methods despite this positive curated evidence. The complete abstract identifies mouse N1E-115 experiments but does not independently resolve the localization assay or introduced-construct species; those limits remain. This contextual enrichment is retained as non-core because a distinct perinuclear mechanism has not been established, not because the pool is contradicted. It can coexist with the independently supported cytosolic pool and does not mean nuclear-membrane lumen. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0198 SUPPORTS TRANSFER The experimentally attributed UniProt localization supports this valid vocabulary transfer. Original assay details remain unverified; that access limitation is not contrary evidence. Supporting Evidence: GO_REF:0000044 GO_REF:0000052 file:human/DOCK6/DOCK6-uniprot.txt Cytoplasm, perinuclear region |
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Download this section (compressed HTML)Q: Which endogenous regulatory inputs permit human DOCK6 to activate Rac1 or CDC42, and explain the difference between earlier positive studies and the negative 2020 biosensor screen?
Q: Does native DOCK6 contact LRCH4 directly, and which interface controls its redistribution without assigning the DOCK7 DHR2 result to DOCK6?
Q: Which cell and construct context supports the curated perinuclear DOCK6 pool, and is that enrichment distinct from its diffuse cytosolic pool?
Experiment: Compare sequence-verified full-length human DOCK6 and its DHR2 region using matched purified exchange assays and cellular Rac1/CDC42 biosensors. Vary phosphorylation state and LRCH coexpression, with expression-matched inactive controls and separate localization readouts.
Hypothesis: Defined regulatory conditions reconcile DOCK6 exchange activity with the negative human-cell biosensor screen.
Type: Matched biochemical and cellular activity assays
Experiment: Test purified components and endogenous reciprocal association, then separate binding-defective from catalytically altered constructs when measuring cytosolic and peripheral pools.
Hypothesis: LRCH4 association controls DOCK6 localization through a specific physical interface.
Type: Interface and localization analysis
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