DOCK8 is a large Rho-family guanine-nucleotide exchange factor that activates CDC42 and couples localized signaling to leukocyte polarization and migration. It moves between cytosolic and leading-edge membrane pools and is restrained by LRCH1 association, with PKCΞ±-dependent phosphorylation promoting release of that inhibition. In human B cells, DOCK8 also provides a signaling adaptor function linking TLR9βMyD88 stimulation to Pyk2 and Src-family kinase signaling. Its functions support immune-cell migration, communication and persistence; loss of DOCK8 causes a combined immunodeficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: DOCK8 is a Rho-family guanine-nucleotide exchange factor. Reason: The target descends from the literal GEF IBD at PTN000593987 in PTHR23317, and its aligned sequence matches current Q8NF50. Experimental descendant grounding includes human DOCK8, mouse Dock8 and fly Zir; the target appearing among the donors is valid. Human DOCK8 cellular Cdc42 activation and the 2012 purified DHR2 exchange assays independently corroborate the inherited activity. The crystal structure and dendritic-cell experiments are separately verified as mouse; the exact kinetic-construct species was not established from the recovered source scope. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000593987 SUPPORTS TRANSFER Literal GEF IBD is on the target lineage; experimental descendant sources and target activity support transfer. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: DOCK8 promotes CDC42 activation through its DHR2 exchange-factor domain. Reason: Human FLAG-DOCK8 constructs and its DHR2 domain support cellular Cdc42 GTP loading and nucleotide-free Cdc42 association. Purified fragments were used for binding competition with LRCH1; this paper is not described as a purified human exchange-rate measurement. The 2012 purified DHR2 exchange assays supply complementary evidence, with separately verified mouse structural and dendritic-cell experiments; the exact kinetic-construct species remains unresolved. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Ortholog and DOCK-family evidence correctly identify GEF activity. Reason: The current IPR026791 entry maps the DOCK family to GEF activity, and mouse Q8C147 has direct IDA evidence from PMID22461490. Human target experiments independently support CDC42 activation. Family descriptions of SH3/ELMO regulation in other DOCK subfamilies are not transferred to DOCK8. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C147 SUPPORTS TRANSFER Current mouse IDA GEF source and human target assays support the electronic inference. |
| GO:0005085 guanyl-nucleotide exchange factor activity | TAS Reactome:R-HSA-9017491 | ACCEPT | Summary: The Reactome catalyst model includes DOCK8 as a GEF. Reason: The exact positive catalyst path includes Q8NF50 residues 1β2099. This event models RHOJ nucleotide exchange and cites PMID15304341; the accessible abstract does not resolve that specific substrate assay, and full original access failed. Independently established CDC42 exchange-factor activity supports the general MF, while RHOJ is not added to the core substrate list. |
| GO:0005515 protein binding | IPI PMID:22581261 DOCK8 functions as an adaptor that links TLR-MyD88 signaling... | MODIFY | Summary: DOCK8 has a signaling adaptor role in the TLR9βMyD88 pathway. Reason: Human B-cell and transfection experiments establish DOCK8 association with MyD88/Pyk2 and a role in Pyk2 activation followed by phosphorylation-dependent Src/Lyn recruitment. Signaling adaptor activity captures this functional association more informatively than generic binding. The data do not establish an obligatory MyD88βPyk2 bridge, a mapped SH2 docking interface or absolute independence from every GEF function. Proposed replacements: signaling adaptor activity Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH2 in the reported assay. Reason: IntAct EBI-8795967/EBI-8797567 for PMID:24255178 report anti-tag AP-MS coassociation in human HEK293 cells with DOCK8 bait. The original cache is abstract-only and publisher recovery failed, so no uninspected target-specific mechanism or purified direct interaction is claimed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH1 in the reported assay. Reason: IntAct EBI-8795967/EBI-8797567 for PMID:24255178 support anti-tag AP-MS coassociation in human HEK293 cells. These spoke-expanded records share an experiment identifier with other partners; pair identity is verified separately. Independent targeted LRCH1 experiments corroborate the association, without converting this AP-MS assay into binary binding. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: DOCK8 binds the DNA-binding transcription factor MEOX2 in a binary assay. Reason: Human MEOX2 P50222 and DOCK8 are identified in the 2014 binary map by array, prey-pooling and validated Y2H records, including EBI-10592216 (IM-23318-39396). The study retained identity-confirmed pairs positive in at least three of four fresh-colony retests. The reference sequence/taxon checks match MEOX2 with its homeobox and independently established DNA-dependent transcriptional activity. GO:0140297 describes binding to that partner class; it does not assign transcriptional regulation to DOCK8. These stages are one study, not independent replications; pair-specific orthogonal validation, native leukocyte coassociation and affinity remain unestablished. Tissue enrichment alone does not contradict the measured binding capacity, and no all-isoform activity is inferred. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: DOCK8 binds the cytoskeletal keratin KRT40 in a binary assay. Reason: Human KRT40 Q6A162 and DOCK8 are identified in the 2014 binary map by array, prey-pooling and validated Y2H records, including EBI-10592226 (IM-23318-39397). The same identity-confirmation and at-least-three-of-four retest criterion applies. KRT40 is an intermediate-filament keratin with an IF rod domain, so GO:0008092 describes the verified partner class without requiring an assembled-filament assay or assigning filament assembly to DOCK8. These are stages of one study; native leukocyte coassociation, pair-specific orthogonal validation and affinity remain unestablished. The reference sequence matches do not independently authenticate every experimental insert or natural product. Proposed replacements: cytoskeletal protein binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: DOCK8 associates with CARHSP1 in the reported assay. Reason: The positive CARHSP1 Q9Y2V2 pair includes validated Y2H EBI-10592236 (IM-23318-39398) and the same screening/retesting stages as MEOX2 and KRT40. It is retained with the same assay confidence. CARHSP1 binds RNA, but binding that protein does not establish RNA binding or RNA regulation by DOCK8; no suitably specific partner-class term was established in the bounded ontology search. The difference in annotation granularity reflects term meaning, not a claim that this interaction is less reproducible. Native context and pair-specific orthogonal validation remain unestablished. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | KEEP AS NON CORE | Summary: DOCK8 associates with PIMREG in the reported assay. Reason: Validated Y2H EBI-16461131 and its associated screening records report positive Y2H interaction and identify a DOCK8 sufficient-binding fragment at residues 1587β2099. This is a construct boundary, not proof that every full-length natural product acts in mitosis. The original isoform-screen Methods describe identity confirmation and repeated pairwise testing. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | MODIFY | Summary: DOCK8 binds its small-GTPase substrate CDC42. Reason: The human target study demonstrates Cdc42 association with DOCK8 DHR2 and competition by LRCH1, including purified fragments. Small GTPase binding preserves the actual molecular recognition claim more specifically than protein binding. Cellular GTP loading separately establishes exchange-factor function; fragment endpoint and mutant-Cdc42 conditions do not constitute a measured native full-length affinity. Proposed replacements: small GTPase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH1 in the reported assay. Reason: Reciprocal tagged co-IP, truncation mapping and purified-component competition establish regulated DOCK8βLRCH1 interaction. LRCH1 competes with CDC42 for DOCK8 DHR2 and restrains its activation: the inhibitor acts on DOCK8, so this evidence does not give DOCK8 inhibitor activity. LRCH1βs calponin-homology domain alone does not establish a cytoskeletal partner class, and no better-supported binding term is substituted. The reported DHR2 endpoint differences across Results, caption and Methods remain explicit in the source notes. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH2 in the reported assay. Reason: BioPlex IntAct EBI-21793331 for PMID:28514442 supports DOCK8-bait AP-MS coassociation in HEK293T cells using C-terminal HA-FLAG tagging. Complex capture is not a purified binary affinity measurement. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH1 in the reported assay. Reason: IntAct EBI-22137937 for PMID:31515488 carries an LRCH1 position 486 variant annotated as having no effect on the tested interaction. It supports the positive pair under that assay, with the partner variant preserved as source context; it does not identify an endogenous regulatory complex. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32203420 Systems analysis of RhoGEF and RhoGAP regulatory proteins re... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH2 in the reported assay. Reason: IntAct EBI-25400409 for PMID:32203420 and Figure 6g support DOCK8βLRCH2 association and its LRR-region dependence. Independently translated library DNA uniquely matches the 2031-residue Q8NF50-3 coding body with vector flanks; the IntAct canonical reference ROGID is not substituted for this insert identity. The same studyβs negative activity-screen summary is condition-specific and does not negate the interaction or universalize inactivity. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH2 in the reported assay. Reason: BioPlex3 IntAct EBI-54710918 supports DOCK8-bait AP-MS coassociation in human 293T cells. The original Methods use sequenced C-terminal FLAG-HA ORFeome constructs and gene-level network aggregation; no natural isoform is assigned from the network alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH1 in the reported assay. Reason: BioPlex3 IntAct EBI-54507168/EBI-54992535 support LRCH1-bait AP-MS coassociation with DOCK8 in human 293T cells. This is consistent with targeted association evidence, while direct interface or natural product identity is not inferred from the spoke-expanded network. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: DOCK8 associates with LRCH1 in the reported assay. Reason: The paper-linked primary U2OS AP-MS graph contains edge 554270 from LRCH1 bait 552520 to DOCK8 prey 552502, with both Ensembl identities verified. This is an actual experimental graph edge, not an embedding prediction; its gene-level resolution does not establish a particular isoform or purified binary affinity. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | MODIFY | Summary: The soluble DOCK8 pool is localized to the cytosol. Reason: The source supports diffuse cytoplasmic DOCK8 before chemokine-driven redistribution. Independent target-specific HPA ICC/IF and the 2020 localization study establish a cytosolic pool, supporting cytosol as the more precise nonexclusive location. This does not erase the separately supported leading-edge membrane pool or imply that every LRCH-dependent redistribution is basal localization. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: The soluble DOCK8 pool is localized to the cytosol. Reason: The source supports diffuse cytoplasmic DOCK8 before chemokine-driven redistribution. Independent target-specific HPA ICC/IF and the 2020 localization study establish a cytosolic pool, supporting cytosol as the more precise nonexclusive location. This does not erase the separately supported leading-edge membrane pool or imply that every LRCH-dependent redistribution is basal localization. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0086 Β· Cytoplasm SUPPORTS TRANSFER Actual UniProt experimental cytoplasmic statement is supported; independent target HPA and localization data resolve a cytosolic pool. Proposed replacements: cytosol |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: DOCK8 has a cytosolic pool. Reason: The HPA record is matched to ENSG00000107099 and Q8NF50 and reports supported cytosol localization in its ICC/IF data. The experimental 2020 study independently finds cytosolic tagged DOCK8 before LRCH-dependent redistribution. HPA data records were inspected; no microscopy-pixel or isoform-specific conclusion is claimed. Supporting Evidence: |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9017491 | ACCEPT | Summary: Reactome places DOCK8 in the cytosol. Reason: The positive event 9017491βcatalyst 9017492βGEF set 9017486βDOCK8 entity 1011619 path resolves to Q8NF50 residues 1β2099 in cytosol. Independent HPA localization corroborates this compartment. The eventβs unresolved RHOJ assay specificity does not invalidate the supported cellular location. |
| GO:0005886 plasma membrane | EXP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | MODIFY | Summary: DOCK8 accumulates at the leading-edge membrane during directed migration. Reason: The cited study expresses human FLAG-DOCK8 in murine T8.1 hybridoma cells. Figure 2H shows chemokine-induced leading-edge redistribution; Figure 6I separately shows redistribution to the cell membrane. Leading-edge membrane refines this demonstrated pool without asserting that all plasma-membrane DOCK8 occupies it. The independent HPA plasma-membrane annotation is retained at its own assay resolution. Proposed replacements: leading edge membrane Supporting Evidence: |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human DOCK8 has a supported plasma-membrane pool. Reason: Target-specific HPA003219 ICC/IF records report plasma-membrane and cytosol localization in human REH, THP-1 and U2OS cells, with supported reliability. Those records do not identify a leading edge, so the source is retained at plasma-membrane resolution. The separately demonstrated leading-edge pool is a subregion of plasma membrane, not a contradiction or an exclusive distribution. No image pixels were independently interpreted. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | MODIFY | Summary: DOCK8 accumulates at the leading-edge membrane during directed migration. Reason: The UniProt cell-membrane statement mapped by SL-0039 cites PMID:28028151. That study directly shows human FLAG-DOCK8 at the leading edge after chemokine stimulation, alongside broader membrane redistribution. The replacement identifies that supported subregion without declaring every plasma-membrane pool equivalent to a leading edge; HPA retains its independent broader endpoint. The electronic source identifier and qualifier are unchanged. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0039 Β· Cell membrane SUPPORTS TRANSFER The experimental UniProt cell-membrane statement is supported. Its cited target study resolves a leading-edge pool, while other plasma-membrane observations remain independently represented. Proposed replacements: leading edge membrane Supporting Evidence: |
| GO:0007264 small GTPase-mediated signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: DOCK8 participates in Rho-family GTPase signaling. Reason: IPR026791 correctly identifies a small-GTPase signaling family, while target CDC42 activation resolves the Rho-family pathway. Rho protein signal transduction is the verified descendant of the broader small-GTPase process; the sign-specific regulatory term is handled separately rather than treating a regulates relation as an is_a edge. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR026791 SUPPORTS TRANSFER Current family mapping is correct but target CDC42 evidence supports a more specific Rho-family pathway. Proposed replacements: Rho protein signal transduction Supporting Evidence: |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Independent human localization supports a plasma-membrane refinement. Reason: The positive NK-cell membrane-proteome assertion is preserved. Its DOCK8-specific table was not recovered; this does not contradict the curatorβs observation. Independent HPA target ICC/IF in human cell lines and PMID:28028151 support plasma membrane as a more informative gene-level location. This synthesis does not identify the original NK fraction, imply that its membrane proteome was restricted to plasma membrane, or assign an unobserved leading edge to those cells. Proposed replacements: plasma membrane Supporting Evidence: |
| GO:0031252 cell leading edge | IBA GO_REF:0000033 | MODIFY | Summary: Inherited leading-edge localization can be resolved to leading-edge membrane. Reason: The literal PTN002762128 IBD lies on the target Euteleostomi lineage and is grounded in mouse and human experiments. Target FLAG-DOCK8 localization supports the membrane subregion. Refinement preserves the ancestral location judgment and does not classify the targetβs own experimental donor entry as circular. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002762128 SUPPORTS TRANSFER Actual target descent and literal leading-edge IBD are verified; target observations resolve the membrane subregion. Proposed replacements: leading edge membrane |
| GO:0031252 cell leading edge | IEA GO_REF:0000107 | MODIFY | Summary: Mouse leading-edge evidence and human target localization support the membrane subregion. Reason: Current mouse Q8C147 records contain direct IDA leading-edge evidence from PMID22461490. The human FLAG-DOCK8 localization study independently supports leading-edge membrane, a verified part_of descendant of cell leading edge. The refinement does not depend on donor count or on reverse ISO records. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8C147 SUPPORTS TRANSFER Direct mouse IDA leading-edge source exists and the human target establishes the membrane subregion. Proposed replacements: leading edge membrane |
| GO:0031256 leading edge membrane | IDA PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: DOCK8 localizes to the leading-edge membrane of stimulated migrating cells. Reason: The source shows human FLAG-DOCK8 redistribution in murine T8.1 hybridoma cells during SDF-1Ξ±-driven polarization and migration. The protein species is human despite the host cell, and the observation is a regulated membrane-associated pool, not a transmembrane-protein or all-isoform claim. Supporting Evidence: |
| GO:0031258 lamellipodium membrane | IEA GO_REF:0000044 | ACCEPT | Summary: DOCK8 has a supported lamellipodium-membrane pool. Reason: UniProt explicitly attributes lamellipodium membrane to the experimental DOCK8 localization source. This positive curated subcompartment is retained without treating it as a synonym for every leading-edge observation. Current GO places lamellipodium membrane below leading-edge membrane, so replacing it by the latter would generalize rather than improve specificity. The localization is nonexclusive and does not establish identical distribution of all natural products. Supporting Evidence: |
| GO:0035023 regulation of Rho protein signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: DOCK8 positively regulates Rho-family signaling through CDC42 activation. Reason: The target genuinely descends from the PTN000593987 IBD; current FlyBase IGI evidence for Zir and the actual donor abstract ground the ancestral regulatory assertion. Human DOCK8-mediated Cdc42 activation supplies the positive sign for target refinement. This is a specificity improvement, not rejection of the deep node or its single listed donor. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000593987 SUPPORTS TRANSFER Literal Rho-regulation IBD and target descent verified; fly IGI donor evidence is genuine and target activity supports positive-sign refinement. Proposed replacements: positive regulation of Rho protein signal transduction Supporting Evidence: |
| GO:0043547 positive regulation of GTPase activity | IDA PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | MODIFY | Summary: DOCK8 activates a GTPase by promoting its GDP-to-GTP transition. Reason: The source demonstrates increased Cdc42 GTP loading with DOCK8 DHR2. Activation of GTPase activity explicitly describes replacement of GDP by GTP and is a verified descendant of the broader positive-regulation term. This does not relabel a GEF as a GTPase-activating protein that accelerates hydrolysis. Proposed replacements: activation of GTPase activity Supporting Evidence: |
| GO:0051056 regulation of small GTPase mediated signal transduction | TAS Reactome:R-HSA-9012999 | MODIFY | Summary: DOCK8 positively regulates Rho-family GTPase signaling. Reason: Reactome includes DOCK8 in the Rho-GTPase activation network. Its RHOJ-specific event is retained as a curated model with unresolved primary assay scope, while independent CDC42 activation establishes the positive Rho-regulatory role. GO:0035025 is an actual is_a/part_of descendant of this broad regulatory term. Proposed replacements: positive regulation of Rho protein signal transduction |
| GO:0061485 memory T cell proliferation | IMP PMID:22006977 DOCK8 deficiency impairs CD8 T cell survival and function in... | KEEP AS NON CORE | Summary: DOCK8 deficiency compromises human memory-T-cell proliferation under tested stimulation. Reason: The original sorts human CD4/CD8 memory subsets and measures CFSE dilution after T-cell-activating beads with or without IL2. Deficient CD8 cells fail to divide and CD4 responses are reduced, with subset/survival differences explicitly discussed. This positive contextual phenotype is retained; it does not establish a separate direct cell-division activity or justify a new proliferation core. Supporting Evidence: PMID:22006977 the corresponding subset from DOCK8-deficient patients failed to divide under these stimulatory conditions |
| GO:1903905 positive regulation of establishment of T cell polarity | IBA GO_REF:0000033 | ACCEPT | Summary: DOCK8 positively regulates T-cell polarity. Reason: The literal PTN002762128 IBD is on the target lineage, with both target and mouse experimental grounding. Human FLAG-DOCK8 promotes SDF-1Ξ±-induced polarization in T8.1 cells, with leading-edge recruitment and uropod CD44 redistribution; mutant constructs impair this response. This is a regulated signaling role, supported by the CDC42 mechanism, rather than a conclusion from disease necessity alone. The human construct and murine host/primary-cell experiments remain distinct. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002762128 SUPPORTS TRANSFER Actual positive-polarity IBD and target descent verified; target and mouse perturbation evidence support the inherited function. Supporting Evidence: |
| GO:1903905 positive regulation of establishment of T cell polarity | IEA GO_REF:0000107 | ACCEPT | Summary: DOCK8 positively regulates T-cell polarity. Reason: Current mouse Q8C147 IMP evidence from PMID28028151 grounds the donor inference, independently of its ISO records. Human FLAG-DOCK8 promotes SDF-1Ξ±-induced polarization in T8.1 cells, with leading-edge recruitment and uropod CD44 redistribution; mutant constructs impair this response. This is a regulated signaling role, supported by the CDC42 mechanism, rather than a conclusion from disease necessity alone. The human construct and murine host/primary-cell experiments remain distinct. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C147 SUPPORTS TRANSFER Actual mouse IMP polarity source and human-construct experiments support transfer. Supporting Evidence: |
| GO:1903905 positive regulation of establishment of T cell polarity | IMP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: DOCK8 positively regulates T-cell polarity. Reason: Human FLAG-DOCK8 promotes SDF-1Ξ±-induced polarization in T8.1 cells, with leading-edge recruitment and uropod CD44 redistribution; mutant constructs impair this response. This is a regulated signaling role, supported by the CDC42 mechanism, rather than a conclusion from disease necessity alone. The human construct and murine host/primary-cell experiments remain distinct. Supporting Evidence: |
| GO:1990869 cellular response to chemokine | IMP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | KEEP AS NON CORE | Summary: DOCK8 participates in the tested chemokine-responsive migration pathway. Reason: The source measures SDF-1Ξ±/CXCL12-responsive redistribution, signaling and migration using human DOCK8 constructs and separate mouse primary T cells. The broad response-to-chemokine assertion is supported, but its contextual scope is not a distinct molecular core beyond the specified exchange-factor, polarity and migration functions. Supporting Evidence: |
| GO:2000406 positive regulation of T cell migration | IBA GO_REF:0000033 | ACCEPT | Summary: DOCK8 positively regulates T-cell migration. Reason: The actual PTN002762128 migration IBD lies on the target lineage with target/mouse grounding. Human DOCK8 expression enhances chemokine-directed T8.1 migration, mutant constructs lose the enhancement, and reconstitution rescues the separate mouse Dock8-deficient T-cell response. Coupled CDC42 activation provides a performed regulatory step. This positive regulation does not imply that DOCK8 itself is a motility motor or that all natural products were tested. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002762128 SUPPORTS TRANSFER Literal positive-T-cell-migration IBD and target descent verified; target and mouse evidence support transfer. Supporting Evidence: |
| GO:2000406 positive regulation of T cell migration | IEA GO_REF:0000107 | ACCEPT | Summary: DOCK8 positively regulates T-cell migration. Reason: Current mouse Q8C147 has a direct IMP source from PMID28028151, separate from back-transferred ISO rows. Human DOCK8 expression enhances chemokine-directed T8.1 migration, mutant constructs lose the enhancement, and reconstitution rescues the separate mouse Dock8-deficient T-cell response. Coupled CDC42 activation provides a performed regulatory step. This positive regulation does not imply that DOCK8 itself is a motility motor or that all natural products were tested. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C147 SUPPORTS TRANSFER Actual mouse IMP migration annotation and human-construct response support the inference. Supporting Evidence: |
| GO:2000406 positive regulation of T cell migration | IMP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: DOCK8 positively regulates T-cell migration. Reason: Human DOCK8 expression enhances chemokine-directed T8.1 migration, mutant constructs lose the enhancement, and reconstitution rescues the separate mouse Dock8-deficient T-cell response. Coupled CDC42 activation provides a performed regulatory step. This positive regulation does not imply that DOCK8 itself is a motility motor or that all natural products were tested. Supporting Evidence: |
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Download this section (compressed HTML)Q: Under which matched regulatory conditions do the natural DOCK8 products activate CDC42, and what explains the negative 2031-residue construct result in the 2020 cellular screen?
Q: What physical interfaces and stoichiometry allow DOCK8 to support Pyk2 activation and phosphorylation-dependent Src/Lyn recruitment without requiring an obligatory MyD88βPyk2 bridge?
Q: Does DOCK8 catalyze RHOJ exchange under a defined physiological or biochemical condition, as modeled by Reactome, and which experiment supports that substrate assignment?
Experiment: Compare all four sequence-verified human products and separately defined DHR2 fragments in matched purified nucleotide-exchange and cellular CDC42 assays. Control expression, phosphorylation and LRCH coexpression, and measure localization independently; retain inactive catalytic and empty-vector controls.
Hypothesis: Regulatory context and construct identity explain differing DOCK8 activity readouts.
Type: Matched biochemical and cellular comparison
Experiment: Combine purified binding measurements and endogenous reciprocal association with interface mutants, then measure Pyk2 activation, DOCK8 phosphorylation and Src/Lyn recruitment separately. Test MyD88 dependence without assuming a fixed ternary bridge.
Hypothesis: Specific DOCK8 interfaces coordinate the Pyk2βSrc signaling assembly.
Type: Mechanistic interaction and signaling analysis
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