# DOCK11 review notes

The 17 imported assertions were reviewed individually. Nine are accepted, three are refined to CDC42 signaling, its regulation and exchange-defined GTPase activation, and five are retained as contextual non-core functions. Source identifiers, evidence codes, qualifiers and supporting entities are unchanged. No NEW annotation is proposed.

The single molecular core is CDC42-directed guanine-nucleotide exchange, with positive filopodium assembly in the demonstrated human T-cell spreading context. Historical human construct activity, mouse ortholog experiments and modern patient-cell/rescue assays are distinguished. The historical AY692226 clone is not sequence-identical to current Q5JSL3, and the original exchange assay used immunoprecipitated protein. The normal abstract-only cache flags remain unchanged even where separately recovered originals were read.

Positive filopodium regulation does not mean every immune-cell state responds identically. The two 2023 human studies show differing protrusion outcomes in defined contexts. The marginal-zone B-cell phenotype remains valid mouse-grounded contextual biology. RCC2 co-complex recovery is retained without transferring the paper's separate direct RAC1/coronin interfaces or inventing a DOCK11 adaptor activity.

The [source and assay guide](#source-and-assay-guide) identifies original Methods, figures, public data records and the historical clone comparison. The primary references support the review; the guide is a locator. The [ClinGen project policy](https://github.com/ai4curation/ai-gene-review/blob/50db4d61a99d7a30369f7bae9c38845894441872/projects/CLINGEN_MENDELIAN.md#curation-instructions) retains a supported generic association as non-core when a justified more specific function has not been established.

Normal fetching and publication caching completed in an isolated workspace. The configured Falcon research attempt failed authentication, and the configured fallback returned an insufficient-quota response. No provider report was fabricated. Manual primary-source review and independent core consultation supplied the evidence. Three donor publication caches already present on main were preserved exactly, and separately retrieved versions were kept distinct. The four added publication caches are genuine normal fetch results.

## Review follow-up

The [review](https://github.com/ai4curation/ai-gene-review/pull/5171#issuecomment-6244088396) prompted an exchange-specific GO:0090630 refinement and explicit CDC42 substrate entries. Current QuickGO confirms the term definition and typed ancestry. The three GEF rows and the activation row now carry an authored RO:0002233 input extension for verified human CDC42 P60953; the original 17 source terms, evidence codes, references, qualifiers and donors remain unchanged. The core records the same substrate and activation process. The revised action tally is 9 ACCEPT, 3 MODIFY and 5 KEEP_AS_NON_CORE. No NEW row is added.

The [reproducible clone comparison](DOCK11-bioinformatics/RESULTS.md) includes exact FASTA snapshots, computed differences, input hashes and a reusable script. The assay guide is consolidated below. No new verbatim publication quotations were added.

## Source and assay guide

DOCK11 has one CDC42 exchange-factor core. The review preserves 17 imported assertions and distinguishes catalytic mechanism, context-dependent cellular effects, and curated source propagation. The primary references support the biological claims; this guide provides their locations and assay boundaries.

## Human mechanism and cell context

| Source and locator | Evidence and limits |
|---|---|
| [PMID:16968698](https://doi.org/10.1074/jbc.M606248200), Methods and Results Figures 4–7; [author-uploaded original](https://www.researchgate.net/publication/6821726_Identification_of_a_DOCK180-related_Guanine_Nucleotide_Exchange_Factor_That_Is_Capable_of_Mediating_a_Positive_Feedback_Activation_of_Cdc42) | Endogenous discovery used mouse P19 cells. A historical human brain/IMAGE-derived DOCK11 clone was expressed in COS7; immunoprecipitated HA-tagged protein promoted CDC42 nucleotide exchange. This is an immunocomplex assay, not purified soluble DOCK11. DHR2 and N-terminal deletions distinguish exchange and active-CDC42 feedback contacts. |
| [PMID:37342957](https://doi.org/10.1056/NEJMoa2210054), main Figure 2 and supplementary Figure S15; [author-hosted article and complete appendix](https://opendata.cemm.at/phd-alumni/Block_Jana_Boztug_2024.pdf) | The article occupies PDF pages 55–67. Appendix pages 14, 18–21 and 27–28 (PDF pages 81, 85–88 and 94–95) describe human cells, knock-in, two Jurkat shRNAs, wild-type/W1707S reconstitution, CCL19-stimulated B-LCL CDC42 pull-down, and T-cell spreading on fibronectin. Figure 2 (PDF page 61) and Figure S15 (PDF page 120) support the positive filopodium role. Wild-type rescue was partial; W1707S failed in the tested Jurkat context. These are cellular assays, not purified exchange measurements. |
| [PMID:36952639](https://pubmed.ncbi.nlm.nih.gov/36952639/), platelet and immune-cell Results and supplementary functional Methods; [accepted manuscript with supplementary material](https://pure.manchester.ac.uk/ws/portalfiles/portal/255404274/DOCK11_paper_Blood.pdf) | Patient platelets show reduced CDC42 activation and altered filopodial-stage responses. Activated patient T cells/B-LCLs and DOCK11-depleted healthy-donor monocyte-derived dendritic cells can instead display excessive abnormal fine protrusions. These outcomes restrict universal claims about the direction of morphology changes; they do not erase the positive filopodium result in the other defined context. |

The current [UniProt Q5JSL3 sequence](https://www.uniprot.org/uniprotkb/Q5JSL3/entry) is 2073 residues and has no alternative-products block. The historical [AY692226.1 clone](https://www.ncbi.nlm.nih.gov/nuccore/AY692226.1) is also 2073 residues but its translation has L376, K740 and E1984 where current Q5JSL3 has F376, N740 and K1984. This is a historical human full-length construct, not an exact current-reference assay. The differences alone do not establish functional loss. Engineered deletions and disease variants are not natural splice products.

## Ortholog and comparative experiments

[PMID:15710388](https://doi.org/10.1016/j.febslet.2005.01.006) is available here as a complete abstract. It reports Zizimin2 binding and activation of CDC42 versus TC10/TCL. The donor identity is independently verified as mouse Dock11 [A2AF47](https://www.uniprot.org/uniprotkb/A2AF47/entry); unreported construct details are not reconstructed from the abstract.

[PMID:22494997](https://pmc.ncbi.nlm.nih.gov/articles/PMC3359169/), Results on full-length/CZH2 constructs and Methods on BMDCs, CDC42 activation and microscopy, provides mouse immune-cell context. The human 293T expression host does not establish the species of every introduced construct. The exact existing repository cache remains abstract-only; a separate genuine full-text retrieval supplied the inspected original passages.

[PMID:25729399](https://pmc.ncbi.nlm.nih.gov/articles/PMC4343071/), Figures 3–5 and conditional-knockout Methods, compares global and B-cell-specific mouse Dock11 deletion. The marginal-zone B-cell compartment decreases while mature follicular B cells are comparatively preserved. Tested LPS proliferation and chemotaxis were unchanged. These observations support contextual B-cell homeostasis and development, without resolving every differentiation-versus-retention step or proving an equivalent human mechanism.

[PMID:25851601](https://pmc.ncbi.nlm.nih.gov/articles/PMC4472020/), comparative GTPase-specificity Results and GST–DHR2 exchange Methods, directly includes DOCK11 controls despite the DOCK10-focused title. The DOCK11 DHR2 preparation activates CDC42 in the tested comparison; the DOCK10 neuronal phenotype is separate. The inspected gift-construct Methods do not establish the DOCK11 template species merely through the provider's name. The existing full repository cache is preserved; selected original passages were read from a separately retrieved full version.

## RCC2 association and cytosol

[PMID:25074804 Figure 3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4179493/#f03), especially the [original panel image](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dde/4179493/25f381283d3a/jcs-127-19-4292-f03.jpg), identifies DOCK11 in the GFP–RCC2 versus GFP SILAC pull-down from HEK293T cells. Panel B reports score 42.35, two peptides and enrichment ratio 7.5. The Methods describe GFP-Trap isolation and mass-spectrometry identification with a false-discovery threshold below 1%. This establishes positive co-complex recovery, not a purified direct DOCK11–RCC2 interface. Subsequent direct RCC2–RAC1/coronin experiments concern different pairs. The current IntAct response did not resolve this particular paper/partner join; that missing service record is not treated as a negative assay.

The cytosol annotation follows the exact Reactome chain: [event R-HSA-1011598](https://reactome.org/content/detail/R-HSA-1011598) → [DOCK-GEFs set 1012978](https://reactome.org/content/detail/1012978) → [DOCK11 entity 1012996](https://reactome.org/content/detail/1012996). The target member is Q5JSL3 residues 1–2073 in cytosol. This is curated modeled localization, not independent microscopy or an exhaustive distribution claim.

## Propagation and term specificity

The [PANTHER PTHR23317 tree](https://www.pantherdb.org/panther/family.do?clsAccession=PTHR23317) contains target leaf PTN002511212, and the ungapped target alignment matches all 2073 current residues. The literal PAINT IBDs are at PTN000593987 for GEF activity and Rho-signal regulation, and PTN002762089 for positive filopodium assembly. Human Q5JSL3 in the latter descendant-evidence set is legitimate target experimental grounding, not circularity. Each source-specific propagation assessment preserves that ancestral interpretation.

[InterPro IPR026791](https://www.ebi.ac.uk/interpro/entry/InterPro/IPR026791/) supplies the verified GEF and small-GTPase-signaling mappings. Target evidence permits [GO:0032488 Cdc42 protein signal transduction](https://www.ebi.ac.uk/QuickGO/term/GO:0032488) as a descendant refinement of GO:0007264, and [GO:0032489 regulation of Cdc42 protein signal transduction](https://www.ebi.ac.uk/QuickGO/term/GO:0032489) as a descendant refinement of GO:0035023. The two refinements respect the separate process and regulation branches. GO:0090630 activation of GTPase activity refines imported GO:0043547 and explicitly describes GDP-to-GTP replacement. The reviewed activation mechanism is exchange. The CDC42 input is recorded with verified human UniProt P60953 on the three imported GEF assertions and on the refined activation assertion; these extensions are authored additions, not inherited GOA fields.

The supported generic RCC2 association remains non-core under the [ClinGen project instruction](https://github.com/ai4curation/ai-gene-review/blob/50db4d61a99d7a30369f7bae9c38845894441872/projects/CLINGEN_MENDELIAN.md#curation-instructions). A more informative activity is not manufactured from co-purification. The four B-cell assertions remain contextual non-core functions. No new annotation is proposed.

## Source access and remaining questions

The effective caches for PMID:16968698, PMID:37342957 and PMID:36952639 remain abstract-only, despite the separately recovered originals described above. PMID:15710388 remains abstract-only with no full-original assay claim. The existing PMID:22494997 abstract and PMID:25851601 full cache are preserved unchanged; their separate retrieved versions remain distinguished. PMID:25074804 and PMID:25729399 provide full text, with the RCC2 figure additionally inspected as an image. The review's short quotations occur once each in the YAML; the access labels are not silently upgraded.

The main unresolved biology is how cell state selects the morphology response to DOCK11–CDC42 perturbation, and whether the RCC2-associated pool involves direct binding with a functional effect on exchange. Matched perturbation/rescue and controlled interaction assays are proposed in the review.

## 2026-10-17 — follow-up source attribution and reproducibility

Corrected the opening action tally and attributed the RCC2 target measurements specifically to the externally inspected Figure 3B panel; the local text cache does not name DOCK11. The historical-clone comparison is now cited directly from the review, and all three control FASTAs and replay commands accompany the saved analysis. No annotation decisions or original source fields changed.