Summary: Conserved B-cell compartment homeostasis is a contextual function.

Reason: Mouse Dock11 A2AF47 has direct IMP grounding in PMID:25729399. Global and B-cell-specific deletion reduce the marginal-zone B-cell compartment; normal LPS proliferation and tested chemotaxis do not invalidate that compartment phenotype. The human transfer is a defensible conserved physiological context, while the central molecular function is CDC42-directed nucleotide exchange. Retain this developmental/homeostatic context as non-core without claiming that a particular human proliferation, survival or retention mechanism has been demonstrated.

Summary: Conserved B-cell compartment homeostasis is a contextual function.

Reason: Mouse Dock11 A2AF47 has direct IMP grounding in PMID:25729399. Global and B-cell-specific deletion reduce the marginal-zone B-cell compartment; normal LPS proliferation and tested chemotaxis do not invalidate that compartment phenotype. The human transfer is a defensible conserved physiological context, while the central molecular function is CDC42-directed nucleotide exchange. Retain this developmental/homeostatic context as non-core without claiming that a particular human proliferation, survival or retention mechanism has been demonstrated.

Summary: Marginal-zone B-cell differentiation is supported by the mouse ortholog.

Reason: PMID:25729399 reports fewer marginal-zone B cells after both global and B-cell-specific Dock11 deletion, with mature follicular B cells comparatively preserved. This supports the curated developmental context and its ortholog transfer. The experiment does not distinguish every step of differentiation from subsequent retention or maintenance, and this cell-type-specific outcome is not a separate molecular core.

Summary: Marginal-zone B-cell differentiation is supported by the mouse ortholog.

Reason: PMID:25729399 reports fewer marginal-zone B cells after both global and B-cell-specific Dock11 deletion, with mature follicular B cells comparatively preserved. This supports the curated developmental context and its ortholog transfer. The experiment does not distinguish every step of differentiation from subsequent retention or maintenance, and this cell-type-specific outcome is not a separate molecular core.

Summary: Phylogenetic GEF activity is directly corroborated on DOCK11.

Reason: DOCK11 promotes CDC42 nucleotide exchange. The recovered PMID:16968698 original measures exchange using immunoprecipitated HA-tagged historical human full-length DOCK11 expressed in COS7, rather than purified soluble DOCK11; the DHR2 fragment is weaker and Rac is negative in the tested comparison. The historical 2073-residue clone differs at three positions from the current reference, without evidence that this negates its gene-level activity. PMID:25851601 separately measures CDC42-selective exchange by a DOCK11 DHR2 preparation. GO:0005085 is the appropriate current activity term. The literal IBD is at PTN000593987 on the verified path to Q5JSL3; the target MSA sequence matches its current 2073-residue sequence. This is a valid ancestral placement, not a pairwise donor vote.

Summary: Combined orthology and domain mapping recover the measured GEF function.

Reason: DOCK11 promotes CDC42 nucleotide exchange. The recovered PMID:16968698 original measures exchange using immunoprecipitated HA-tagged historical human full-length DOCK11 expressed in COS7, rather than purified soluble DOCK11; the DHR2 fragment is weaker and Rac is negative in the tested comparison. The historical 2073-residue clone differs at three positions from the current reference, without evidence that this negates its gene-level activity. PMID:25851601 separately measures CDC42-selective exchange by a DOCK11 DHR2 preparation. GO:0005085 is the appropriate current activity term.

Summary: Curated mouse-to-human transfer of GEF activity is supported.

Reason: DOCK11 promotes CDC42 nucleotide exchange. The recovered PMID:16968698 original measures exchange using immunoprecipitated HA-tagged historical human full-length DOCK11 expressed in COS7, rather than purified soluble DOCK11; the DHR2 fragment is weaker and Rac is negative in the tested comparison. The historical 2073-residue clone differs at three positions from the current reference, without evidence that this negates its gene-level activity. PMID:25851601 separately measures CDC42-selective exchange by a DOCK11 DHR2 preparation. GO:0005085 is the appropriate current activity term.

Summary: DOCK11 was recovered with GFP–RCC2 in a controlled cellular pull-down.

Reason: PMID:25074804 Figure 3B identifies DOCK11 in the HEK293T GFP–RCC2 versus GFP SILAC screen (score 42.35, two peptides, enrichment ratio 7.5). This is positive co-complex association, not a purified binary interface or a demonstrated DOCK11 regulatory effect on RCC2. The subsequent direct RCC2–RAC1 and RCC2–coronin assays should not be reassigned to DOCK11. Retain the positive generic association under the ClinGen project policy; a more specific DOCK11 activity or direct partner-class interaction is not established by this multiprotein recovery.

Summary: The Reactome model places the full DOCK11 participant in cytosol.

Reason: The exact curated chain is R-HSA-1011598 → DOCK-GEFs set 1012978 → member 1012996, the Q5JSL3 1–2073 entity assigned to cytosol. This establishes the provenance of the imported TAS location. It is a modeled cytosolic pool, not an independent microscopy result, an exhaustive distribution, or evidence that all DOCK11 is permanently soluble.

Summary: Specify the experimentally supported CDC42 signaling branch.

Reason: The InterPro family mapping to small-GTPase signaling is biologically sound but broader than the established target specificity. DOCK11 catalyzes the GDP-exchange step that activates CDC42; the human construct assay and human-cell activation phenotypes therefore place the protein in the CDC42 signaling cassette. GO:0032488 is an is_a/part_of descendant of the imported GO:0007264 in the checked current ontology. This refines an existing assertion without adding a new process or transferring the functions of every DOCK family member.

Proposed replacements: Cdc42 protein signal transduction

Summary: Binding to the small GTPase CDC42 is integral to the exchange mechanism.

Reason: The verified mouse donor carries a direct CDC42-binding annotation, and the recovered human DOCK11 study distinguishes binding to nucleotide-depleted CDC42 through DHR2 from binding to active CDC42 requiring additional N-terminal sequence. These are target–substrate/feedback interactions within the GEF mechanism, not a separate generic scaffold function. The existing small-GTPase-binding term is supported without claiming binding to every small GTPase.

Summary: Refine Rho-family signaling regulation to its CDC42 branch.

Reason: The literal GO:0035023 IBD at PTN000593987 includes the target lineage and is valid broad Rho-family evidence. DOCK11-specific exchange and active-CDC42 measurements identify the CDC42 regulatory branch, represented by GO:0032489, a checked typed descendant of GO:0035023. This is increased specificity, not rejection of a single-donor ancestral judgment and not a claim that DOCK11 acts on RHOA or RAC1.

Proposed replacements: regulation of Cdc42 protein signal transduction

Summary: Specify exchange-mediated CDC42 activation.

Reason: DOCK11 increases GTP-loaded CDC42 by nucleotide exchange. The current GO:0090630 definition explicitly describes initiation of GTPase activity by GDP-to-GTP replacement and is an is_a/part_of descendant of GO:0043547. It therefore captures the demonstrated activation mechanism more precisely than the imported broad positive-regulation term. Mouse donor evidence and independent human DOCK11 experiments support the same mechanism. The authored CDC42 input extension records the human target substrate without changing the original donor or evidence provenance.

Proposed replacements: activation of GTPase activity

Summary: The filopodium IBA is grounded in direct target and ortholog evidence.

Reason: Positive filopodium regulation is directly supported in defined cellular contexts. In PMID:37342957, patient and engineered human cells show impaired actin-rich protrusions, and Jurkat knockdown/rescue shows partial restoration by wild-type DOCK11 but not W1707S during the tested spreading response. PMID:36952639 reports reduced platelet filopodial-stage responses alongside excessive abnormal protrusions in other activated immune-cell settings. Thus the positive process annotation is supported, but is not a universal prediction that DOCK11 deficiency reduces every protrusion in every cell state. The GO:0051491 IBD lies at PTN002762089 on the target path and includes human Q5JSL3 as genuine descendant experimental grounding; this self-inclusion is not circular.

Summary: Orthology transfer of positive filopodium regulation is corroborated in human cells.

Reason: Positive filopodium regulation is directly supported in defined cellular contexts. In PMID:37342957, patient and engineered human cells show impaired actin-rich protrusions, and Jurkat knockdown/rescue shows partial restoration by wild-type DOCK11 but not W1707S during the tested spreading response. PMID:36952639 reports reduced platelet filopodial-stage responses alongside excessive abnormal protrusions in other activated immune-cell settings. Thus the positive process annotation is supported, but is not a universal prediction that DOCK11 deficiency reduces every protrusion in every cell state.

Summary: The cited human study directly supports positive filopodium assembly.

Reason: Positive filopodium regulation is directly supported in defined cellular contexts. In PMID:37342957, patient and engineered human cells show impaired actin-rich protrusions, and Jurkat knockdown/rescue shows partial restoration by wild-type DOCK11 but not W1707S during the tested spreading response. PMID:36952639 reports reduced platelet filopodial-stage responses alongside excessive abnormal protrusions in other activated immune-cell settings. Thus the positive process annotation is supported, but is not a universal prediction that DOCK11 deficiency reduces every protrusion in every cell state. The separately recovered original and appendix include fibronectin-spreading microscopy, two Jurkat shRNAs and wild-type/variant reconstitution; the normal cache remains abstract-only. These are cellular perturbation/rescue assays, not a purified nucleotide-exchange assay.

Summary: Curated filopodium transfer agrees with the directly assayed human function.

Reason: Positive filopodium regulation is directly supported in defined cellular contexts. In PMID:37342957, patient and engineered human cells show impaired actin-rich protrusions, and Jurkat knockdown/rescue shows partial restoration by wild-type DOCK11 but not W1707S during the tested spreading response. PMID:36952639 reports reduced platelet filopodial-stage responses alongside excessive abnormal protrusions in other activated immune-cell settings. Thus the positive process annotation is supported, but is not a universal prediction that DOCK11 deficiency reduces every protrusion in every cell state.