DIAPH3 is a Rho-regulated diaphanous-related formin that binds actin and promotes filament assembly. Its FH1–FH2 region supports actin filament growth and bundling, while terminal regulatory regions restrain assembly activity. DIAPH3 also associates with microtubules; mDia2 fragment experiments separate microtubule binding and stabilization from actin assembly. Human DIAPH3 occupies cytosolic and cytoskeletal pools and accumulates at the cleavage furrow and spindle midzone during cytokinesis. Regulated nuclear transport and membrane recruitment provide additional cellular contexts. Increased DIAPH3 activity is associated with auditory neuropathy. Multiple natural splice products differ in regulatory and C-terminal sequences, and their individual activities are not established by the historical engineered constructs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000813 ESCRT I complex | IEA GO_REF:0000107 | REMOVE | Summary: The ESCRT-I complex assignment confuses regulation with complex membership. Reason: The Ensembl transfer is traceable to mouse Q9Z207, whose current part_of/IMP source is PMID:33036023. The actual original tests mDia2 loss and rescue in mouse erythroid cells and places mDia2 upstream of SRF-dependent Chmp5 expression and ESCRT-III-mediated remodeling. The source does not establish mDia2 as a subunit of ESCRT-I, the class-E sorting complex specified by GO:0000813. This is a source-to-complex mapping error, not evidence that DIAPH3 has no effect on endosomal biology. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q9Z207 SOURCE BAD Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The cited experimental source was read; the error concerns its annotation-to-location or complex role, not the paper quality or orthology. ensembl:ENSMUSP00000129420 SOURCE BAD Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The cited experimental source was read; the error concerns its annotation-to-location or complex role, not the paper quality or orthology. Supporting Evidence: PMID:33036023 loss of mDia2 significantly reduced the binding of SRF to the SRE on Chmp5 file:human/DIAPH3/DIAPH3-source-guide.md |
| GO:0000922 spindle pole | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain a specialized spindle-pole localization inferred from mouse. Reason: The actual Q9Z207 donor source PMID:24069443 detects endogenous mDia2 with pericentrin at spindle poles of fresh and vitrified-warmed mouse MII oocytes, with IgG controls. This supports the transferred location, while the oocyte-specific setting is distinct from the general actin-assembly and microtubule-binding functions. It does not identify a human splice product or establish a microtubule-nucleating activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Supporting Evidence: |
| GO:0003779 actin binding | IEA GO_REF:0000120 | ACCEPT | Summary: Actin binding is a core property of DIAPH3. Reason: The combined electronic source contains valid mouse-ortholog and InterPro matches. Current Q9NSV4 has IPR010472 at residues 302–488 and IPR010473 at 113–297; these are gene-product mappings, not evidence that either isolated regulatory domain is the actin-binding site. Independent mDia2 FH2 biochemistry supports filament binding and assembly, and the historical human construct in PMID:18755006 promotes filopodia. The FH2-containing protein mechanism supports this annotation without transferring every activity to every splice product. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. InterPro:IPR010472 SUPPORTS TRANSFER Actual current target-domain match and official InterPro2GO mapping checked; the whole-protein mechanism, not an isolated regulatory domain, supports the refinement. InterPro:IPR010473 SUPPORTS TRANSFER Actual current target-domain match and official InterPro2GO mapping checked; the whole-protein mechanism, not an isolated regulatory domain, supports the refinement. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain regulated nuclear localization. Reason: The mouse Q9Z207 donor has direct nuclear-localization evidence from PMID:19117945 and PMID:23558171. The accessible complete abstract of PMID:19117945 describes endogenous mDia2 accumulation after CRM1 inhibition, a functional nuclear-localization sequence, and importin-dependent transport; it does not specify all construct/host details. Together with the curated ortholog assignment, this supports nucleus localization in a regulated trafficking context. No finer nuclear compartment or equivalence among all seven human products is inferred. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER Imported subcellular mapping retained; independent target imaging supports the stated location/refinement. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain regulated nuclear localization. Reason: The mouse Q9Z207 donor has direct nuclear-localization evidence from PMID:19117945 and PMID:23558171. The accessible complete abstract of PMID:19117945 describes endogenous mDia2 accumulation after CRM1 inhibition, a functional nuclear-localization sequence, and importin-dependent transport; it does not specify all construct/host details. Together with the curated ortholog assignment, this supports nucleus localization in a regulated trafficking context. No finer nuclear compartment or equivalence among all seven human products is inferred. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. |
| GO:0005737 cytoplasm | EXP PMID:18755006 Filopodia formation induced by active mDia2/Drf3. | MODIFY | Summary: Refine the diffuse cytoplasmic pool to cytosol. Reason: The separately recovered full original PMID:18755006 describes the historical human full-length construct as cytosolic in B16-F1 cells. That 1110-residue construct was assembled from human cDNAs and is not equated with the current 1193-residue displayed product. Cytosol is more informative than cytoplasm for the observed diffuse pool; activated deletion constructs additionally accumulate at filopodial tips. Existing Reactome cytosol assertions already cover the replacement location. Proposed replacements: cytosol Supporting Evidence: |
| GO:0005737 cytoplasm | EXP PMID:19457867 Ubiquitin-mediated degradation of the formin mDia2 upon comp... | MODIFY | Summary: Refine the mitotic cytoplasmic localization to cleavage furrow and spindle midzone. Reason: The actual original PMID:19457867 immunostains endogenous protein in human HeLa cells and explicitly reports colocalization with the actin-rich cleavage furrow and microtubule-rich central spindle during cytokinesis. GO:0051233 denotes the spindle midzone where opposite-pole microtubules overlap. These source-specific locations improve the broad cytoplasm assertion. The endogenous localization experiment is separate from the engineered mDia2 fragment-expression experiment and does not resolve a natural human isoform. Proposed replacements: cleavage furrow spindle midzone Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Summary: Refine the broadly mapped cytoplasmic pool to cytosol. Reason: The imported ortholog/subcellular mapping is biologically consistent with a predominantly cytoplasmic formin that can shuttle to the nucleus. Human-construct imaging in PMID:18755006 and the explicit Q9NSV4 cytosolic entities in Reactome support cytosol as the more informative location. The narrower term is already represented in the source set; this is a refinement of the broad assertion, not additional biological coverage or a claim that all DIAPH3 is permanently cytosolic. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Imported subcellular mapping retained; independent target imaging supports the stated location/refinement. Proposed replacements: cytosol Supporting Evidence: |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Summary: Refine the broadly mapped cytoplasmic pool to cytosol. Reason: The imported ortholog/subcellular mapping is biologically consistent with a predominantly cytoplasmic formin that can shuttle to the nucleus. Human-construct imaging in PMID:18755006 and the explicit Q9NSV4 cytosolic entities in Reactome support cytosol as the more informative location. The narrower term is already represented in the source set; this is a refinement of the broad assertion, not additional biological coverage or a claim that all DIAPH3 is permanently cytosolic. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Proposed replacements: cytosol Supporting Evidence: |
| GO:0005815 microtubule organizing center | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the specialized microtubule-organizing-center localization. Reason: The direct mouse source PMID:24069443 shows mDia2/pericentrin colocalization both at meiotic spindle poles and at cytoplasmic organizing centers during warming of vitrified oocytes. This is genuine location evidence for the ortholog transfer and is not contradicted by the separate human spindle-midzone observation. The annotation does not make DIAPH3 a gamma-tubulin nucleator or imply that this location is constitutive in human cells. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Supporting Evidence: |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5666070 | ACCEPT | Summary: Retain the explicitly modeled cytosolic DIAPH3 pool. Reason: The actual Reactome event R-HSA-5666070 reaches human UniProt Q9NSV4 through input set 5666066 → DIAPH3 dimer 5666128 → protein 5666125; protein 5666125 spans residues 1–1193 and explicitly has cytosol as its compartment. DIAPH3 is a resolved member, not merely an unrelated effector candidate. Cytosol describes the pool recruited to the membrane-associated GTPase; the event does not assert DIAPH3 kinase/GTPase catalysis or the same localization for every alternative product. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013009 | ACCEPT | Summary: Retain the explicitly modeled cytosolic DIAPH3 pool. Reason: The actual Reactome event R-HSA-9013009 reaches human UniProt Q9NSV4 through input set 9013003 hasMember → DIAPH3 dimer 5666128 → protein 5666125; protein 5666125 spans residues 1–1193 and explicitly has cytosol as its compartment. DIAPH3 is a resolved member, not merely an unrelated effector candidate. Cytosol describes the pool recruited to the membrane-associated GTPase; the event does not assert DIAPH3 kinase/GTPase catalysis or the same localization for every alternative product. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9690493 | ACCEPT | Summary: Retain the explicitly modeled cytosolic DIAPH3 pool. Reason: The actual Reactome event R-HSA-9690493 reaches human UniProt Q9NSV4 through input set 9690490 hasMember → protein 5666125; protein 5666125 spans residues 1–1193 and explicitly has cytosol as its compartment. DIAPH3 is a resolved member, not merely an unrelated effector candidate. Cytosol describes the pool recruited to the membrane-associated GTPase; the event does not assert DIAPH3 kinase/GTPase catalysis or the same localization for every alternative product. |
| GO:0005884 actin filament | IBA GO_REF:0000033 | ACCEPT | Summary: Actin-filament association is a conserved core localization. Reason: The actual PAINT IBD at PANTHER:PTN000575131 places actin-filament localization at the family root. Human Q9NSV4 descends from this node through the DIAPH3 branch. Its named donor WBGene00019030 resolves to C. elegans EXC-6/Q9TYU9, whose direct filamentous-actin annotation cites PMID:25771894. The complete abstract documents regulation of actin and microtubule structures during tubulogenesis, while the exact donor localization assay remains curator-supported. Human cellular assembly evidence and mDia2 filament-binding biochemistry independently fit the inherited localization. The deep placement, not donor count, is the basis for acceptance. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000575131 SUPPORTS TRANSFER Actual IBD placed at this family-root node; the human PTN002509309 lineage descends from it. This is an ancestral placement, not pairwise donor voting. WB:WBGene00019030 SUPPORTS TRANSFER Resolves to C. elegans EXC-6/Q9TYU9 and its filamentous-actin IDA annotation to PMID:25771894. The abstract and current curated record support the placement; the exact localization experiment was not independently recovered. Supporting Evidence: file:human/DIAPH3/DIAPH3-source-guide.md |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain experimentally observed plasma-membrane localization. Reason: The current HPA target page reports supported plasma-membrane staining with antibody HPA032151 in A-431, U-251MG and U2OS cells. This is consistent with a recruited peripheral formin pool. It does not imply an integral membrane protein, resolve alternative products, or establish a separate membrane-receptor function. Retain the IDA observation as contextual localization. Supporting Evidence: file:human/DIAPH3/DIAPH3-source-guide.md |
| GO:0007010 cytoskeleton organization | IEA GO_REF:0000107 | MODIFY | Summary: Refine broad cytoskeleton organization to actin-filament polymerization. Reason: The mouse source for this broad mapping is PMID:23558171, which assigns mDia-dependent actin assembly to the nuclear response; its abstract supports the mechanism but does not identify an exact human product. The actin-polymerization mechanism is independently supported by mDia2 fragment biochemistry and the human cellular assembly study. GO:0030041 is a supported specific process already present in this source set. The refinement does not turn downstream transcriptional effects into a new process annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Proposed replacements: actin filament polymerization |
| GO:0007010 cytoskeleton organization | ISS GO_REF:0000024 | MODIFY | Summary: Refine broad cytoskeleton organization to actin-filament polymerization. Reason: The mouse source for this broad mapping is PMID:23558171, which assigns mDia-dependent actin assembly to the nuclear response; its abstract supports the mechanism but does not identify an exact human product. The actin-polymerization mechanism is independently supported by mDia2 fragment biochemistry and the human cellular assembly study. GO:0030041 is a supported specific process already present in this source set. The refinement does not turn downstream transcriptional effects into a new process annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Proposed replacements: actin filament polymerization |
| GO:0008017 microtubule binding | IEA GO_REF:0000107 | ACCEPT | Summary: Microtubule binding is a distinct conserved molecular function. Reason: The source transfer resolves to the curated mouse Q9Z207 assignment and its PMID:18458159 IDA/IMP assertions. The actual original assays purified mDia2 FH1FH2 fragments, with microtubule-dependent cosedimentation controls, saturable binding, and retained binding/stabilization in actin-defective mutants. Its historical construct provenance does not explicitly resolve the template species, so the curated donor identity and the biochemical assay are distinguished. Together with endogenous human spindle localization in PMID:19457867, the evidence supports the conserved function. Exact equivalence to current human products, tubulin-dimer binding and autonomous plus-end capping are not established. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The donor annotation is mouse-specific; the exact species of the historical biochemical fragment remains unresolved in the selected Methods. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The donor annotation is mouse-specific; the exact species of the historical biochemical fragment remains unresolved in the selected Methods. |
| GO:0008092 cytoskeletal protein binding | IEA GO_REF:0000107 | MODIFY | Summary: Replace generic cytoskeletal-protein binding with actin binding. Reason: The traceable mouse donor source PMID:16556604 directly studies the FH2-dependent engagement and bundling of actin filaments. Actin binding describes this source more specifically than binding any cytoskeletal protein. The separate microtubule-binding function is independently supported and already annotated; it is not substituted for the actin substrate measured in this source. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Proposed replacements: actin binding Supporting Evidence: |
| GO:0015630 microtubule cytoskeleton | IDA GO_REF:0000052 | MODIFY | Summary: Refine microtubule cytoskeleton to the microtubule itself. Reason: The actual HPA target page reports supported microtubule staining in A-431, U-251MG and U2OS cells with HPA032151. GO:0005874 describes the tubulin polymer, which is more specific than the entire microtubule cytoskeleton. This localization is concordant with independent ortholog microtubule-binding biochemistry, but the HPA assay itself does not measure binding or resolve splice products. Proposed replacements: microtubule Supporting Evidence: file:human/DIAPH3/DIAPH3-source-guide.md |
| GO:0030036 actin cytoskeleton organization | IEA GO_REF:0000120 | MODIFY | Summary: Refine actin-cytoskeleton organization to filament polymerization. Reason: The broad actin-organization assertion is sound. Current IPR010473 maps to actin-cytoskeleton organization, and the ortholog annotation is grounded in mDia-dependent actin assembly. Direct mDia2 biochemistry and the historical human construct establish the more specific assembly mechanism represented by GO:0030041. This replacement is already present in the source annotations and does not create a separate downstream or redundant NEW process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. InterPro:IPR010473 SUPPORTS TRANSFER Actual current target-domain match and official InterPro2GO mapping checked; the whole-protein mechanism, not an isolated regulatory domain, supports the refinement. Proposed replacements: actin filament polymerization |
| GO:0030036 actin cytoskeleton organization | ISS GO_REF:0000024 | MODIFY | Summary: Refine actin-cytoskeleton organization to filament polymerization. Reason: The broad actin-organization assertion is sound. Current IPR010473 maps to actin-cytoskeleton organization, and the ortholog annotation is grounded in mDia-dependent actin assembly. Direct mDia2 biochemistry and the historical human construct establish the more specific assembly mechanism represented by GO:0030041. This replacement is already present in the source annotations and does not create a separate downstream or redundant NEW process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Proposed replacements: actin filament polymerization |
| GO:0030041 actin filament polymerization | IBA GO_REF:0000033 | ACCEPT | Summary: Accept the ancestral actin-polymerization function. Reason: The actual IBD is placed at PANTHER:PTN000575131, with human Q9NSV4 inside the inheriting DIAPH3 lineage. The listed MGI donors resolve to mouse Diaph1/O08808, Diaph2/O70566 and Diaph3/Q9Z207. Independent direct records and construct-dependent assembly results support the ancestral mechanism; the historical zebrafish identifier was not resolved in the current tree and is not counted as negative evidence. Current Q9Z207 records to PMID:23034183 should not be treated as positive RhoD-driven mDia2 evidence: the actual paper assigns that particular response to mDia3C and includes negative mDia2 controls. Independent PMID:23558171 and the direct assembly literature preserve the overall phylogenetic grounding. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1194490 SUPPORTS TRANSFER Mapped mouse Diaph1/Diaph2 donor with experimental polymerization records, including construct-dependent evidence in PMID:14992721; not assumed to be a one-to-one DIAPH3 ortholog. MGI:MGI:1858500 SUPPORTS TRANSFER Mapped mouse Diaph1/Diaph2 donor with experimental polymerization records, including construct-dependent evidence in PMID:14992721; not assumed to be a one-to-one DIAPH3 ortholog. MGI:MGI:1927222 SUPPORTS TRANSFER Mouse Diaph3/Q9Z207. PMID:23558171 and independent assembly literature support the mechanism; the RhoD-specific mDia2 response is negative in PMID:23034183 and is not counted as positive grounding. PANTHER:PTN000575131 SUPPORTS TRANSFER Actual IBD placed at this family-root node; the human PTN002509309 lineage descends from it. This is an ancestral placement, not pairwise donor voting. ZFIN:ZDB-GENE-090115-1 UNRESOLVED Historical zebrafish identifier not recovered in the current tree; no negative biological inference is made from this tracing gap. Supporting Evidence: file:human/DIAPH3/DIAPH3-source-guide.md |
| GO:0030041 actin filament polymerization | IEA GO_REF:0000107 | ACCEPT | Summary: Actin-filament polymerization is a principal DIAPH3 process. Reason: The mouse-ortholog mapping agrees with mDia2 fragment assembly assays and the historical human construct that induces filopodia. The gene product binds actin and contributes directly to assembly, rather than merely being required as a substrate or acting through an unrelated downstream phenotype. Source-specific construct and isoform limits remain: neither these experiments nor the ortholog transfer establish equal activity of all seven natural human products. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. |
| GO:0030041 actin filament polymerization | ISS GO_REF:0000024 | ACCEPT | Summary: Actin-filament polymerization is a principal DIAPH3 process. Reason: The mouse-ortholog mapping agrees with mDia2 fragment assembly assays and the historical human construct that induces filopodia. The gene product binds actin and contributes directly to assembly, rather than merely being required as a substrate or acting through an unrelated downstream phenotype. Source-specific construct and isoform limits remain: neither these experiments nor the ortholog transfer establish equal activity of all seven natural human products. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. |
| GO:0031267 small GTPase binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Retain small-GTPase binding as regulatory engagement. Reason: The current Q9NSV4 IPR010473 match covers the GTPase-binding regulatory region and the official mapping is small GTPase binding. Independent mDia2 experiments use nucleotide-loaded RhoA and a Rho-binding-defective V180D mutant to connect GTPase engagement with localization and activation. This is a supported regulatory interaction within the formin mechanism, not DIAPH3 GTPase, GEF or GAP activity; broad binding to every small GTPase is not implied. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR010473 SUPPORTS TRANSFER Actual current target-domain match and official InterPro2GO mapping checked; the whole-protein mechanism, not an isolated regulatory domain, supports the refinement. Supporting Evidence: |
| GO:0032154 cleavage furrow | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain cleavage-furrow localization during cytokinesis. Reason: The actual mouse donor source PMID:20660154 localizes endogenous mDia2 at the equatorial cleavage furrow in NIH3T3 cells, with Rho/anillin-dependent redistribution and rescue controls. Human HeLa staining in PMID:19457867 independently supports this location. It is a cell-cycle-specific deployment of the actin machinery, rather than an additional molecular function or a claim that all DIAPH3 products occupy the furrow. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. |
| GO:0032432 actin filament bundle | IEA GO_REF:0000107 | ACCEPT | Summary: Retain actin-filament-bundle association. Reason: The mouse donor PMID:16556604 measures actin side binding and bundle formation with mDia2 FH2-containing fragments using sedimentation and microscopy. Bundling and barbed-end assembly can be experimentally separated, but both involve the same formin actin-engagement machinery. This supports the transferred bundle location while retaining the in vitro fragment scope and avoiding assignment of identical function to all human products. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. Supporting Evidence: |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain homodimerization as a structural property of the formin. Reason: The mouse source PMID:16556604 characterizes dimeric FH2 constructs; PMID:18458159 independently compares their gel-filtration behavior with W630A, which is impaired in stable dimer formation and actin assembly. This supports a structural feature of the actin-assembly mechanism. It is not a second core binding activity, and the experiments do not show that every natural human splice product forms the same dimer. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z207 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. ensembl:ENSMUSP00000129420 SUPPORTS TRANSFER Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | KEEP AS NON CORE | Summary: Retain the curated cadherin-associated observation with proximity-assay limits. Reason: PMID:25468996 uses E-cadherin-BirA* proximity labeling and quantitative proteomics in human MKN28 cells, with parental controls and replicate/enrichment criteria. The actual Methods and Results explicitly include proteins near E-cadherin through direct or indirect associations; this is not a purified binary-binding assay. The source-specific DIAPH3 supplementary-table row was not independently recovered, so the positive HDA target assignment remains curator-supported. Retain the association as non-core without claiming a demonstrated cadherin-binding interface or a separate adhesion mechanism. |
| GO:0097470 ribbon synapse | IEA GO_REF:0000107 | REMOVE | Summary: The transferred ribbon-synapse location is not established by its source assay. Reason: The current mouse donor IDA cites PMID:23441200. In the actual original, a mouse Diap3 transgene causes substantial overexpression, and the ribbon assay stains CtBP2/ribeye and counts presynaptic puncta. It does not stain Diap3 at the ribbons. The authors also distinguish the timing of ribbon loss from stereociliary defects and allow a secondary effect. Transfer of that perturbation phenotype into an is_active_in ribbon-synapse assertion is not justified. This rejects this source-to-location mapping, not the possibility that DIAPH3 affects synapses. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q9Z207 SOURCE BAD Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The cited experimental source was read; the error concerns its annotation-to-location or complex role, not the paper quality or orthology. ensembl:ENSMUSP00000129420 SOURCE BAD Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The cited experimental source was read; the error concerns its annotation-to-location or complex role, not the paper quality or orthology. Supporting Evidence: PMID:23441200 stained using an antibody against CtBP2 file:human/DIAPH3/DIAPH3-source-guide.md |
| GO:1990427 stereocilia tip-link density | IEA GO_REF:0000107 | REMOVE | Summary: The transferred stereocilia tip-link-density location is not established by its source assay. Reason: The mouse donor source PMID:23441200 uses phalloidin to visualize stereociliary actin cores and scanning electron microscopy to examine abnormal stereocilia after Diap3 overexpression. The exact GO term is an electron-dense plaque at either end of a tip link. These experiments neither label Diap3 at that plaque nor identify it as a plaque component. Structural abnormalities and hearing impairment do not establish this highly specific location. No claim of universal absence from stereocilia is made. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q9Z207 SOURCE BAD Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The cited experimental source was read; the error concerns its annotation-to-location or complex role, not the paper quality or orthology. ensembl:ENSMUSP00000129420 SOURCE BAD Mouse Diaph3/mDia2 Q9Z207; the current official Ensembl protein cross-reference is ENSMUSP00000129420.2. The cited experimental source was read; the error concerns its annotation-to-location or complex role, not the paper quality or orthology. |
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Download this section (compressed HTML)Q: Which current DIAPH3 natural products retain regulated actin assembly and microtubule binding, and which exact sequences correspond to the historical mDia2 fragments?
Q: Does endogenous human DIAPH3 physically occupy auditory ribbon synapses or tip-link densities, rather than influencing their morphology through cytoskeletal activity?
Experiment: Compare sequence-verified natural DIAPH3 products in purified actin and microtubule binding/assembly assays, with matched expression and folding controls.
Experiment: Use validated endogenous DIAPH3 tagging and ultrastructural localization in hair cells to test the proposed precise auditory locations separately from overexpression phenotypes.
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