DCC

Summary: DCC contributes to neuronal migration as a conserved guidance receptor.

Reason: The human DCC leaf lies below the actual PTN008454813 IBD for neuron migration. Its mouse Dcc source resolves to P70211 and a current IMP annotation from PMID16267219. The recovered original shows DCC expression on spinal accessory motor neurons and quantified cell-body migration defects in Dcc-null embryos (Methods, Figures 4–5 and Results). This is positive receptor-mediated participation, not merely a generic disease phenotype. Retain the phylogenetic transfer with mouse developmental context; no direct human-neuron experiment is claimed.

Summary: DCC transduces netrin signals across the membrane.

Reason: The netrin-specific receptor child is more informative than generic transmembrane signaling. The recovered author chapter reports rat DCC binding chick netrin-1 in human 293 cells and antibody inhibition of netrin-dependent rat spinal axon outgrowth. This supports the established receptor function and human TAS with curator deference, not a direct human-neuron assay. The same antibody did not block turning within explants; retain that limitation rather than selecting the chemoattraction child solely from outgrowth. No receptor tyrosine-kinase activity is inferred.

Proposed replacements: netrin receptor activity

Summary: MAZ is a DNA-binding transcription factor associated with the DCC cytoplasmic region.

Reason: The complete PMID11527412 abstract explicitly reports in vivo and in vitro association and a confirming yeast two-hybrid assay. The official P56270 record establishes the DNA-binding transcription-factor class. Sixteen RIKEN deposits identify human DCC constructs linked to this paper, but do not expose the original assay details or establish the exact tested MAZ product. Retain the curated positive association with that access limit and refine its partner class. This does not assert that DCC itself binds DNA or activates transcription. GO:0140297 classifies the individual interacting protein. By contrast, GO:0043022 denotes binding to the ribosomal particle, so a ribosomal protein identity alone would not establish that assembled-complex association; the translation study supplies separate fractionation evidence.

Proposed replacements: DNA-binding transcription factor binding

Summary: DCC associates with APPL1/DIP13alpha in an apoptotic signaling context.

Reason: Human APPL1 (DIP13alpha, Q9UKG1) association is supported by mapped yeast two-hybrid interaction and reciprocal co-immunoprecipitation in transfected DLD1 cells. DCC residues 1240–1273 and the APPL1 PTB-containing region were implicated. Functional perturbation links the pair to DCC-dependent death, but this pair assertion does not by itself identify a coordinated multi-component signaling activity or a verified narrower partner-binding term. The separate proapoptotic core description additionally uses recruitment and cell-extract experiments in PMID11248093, but assigns no distinct adaptor molecular function; it does not replace this APPL1-specific IPI assertion. Retain the supported generic interaction under the user's explicit ClinGen project instruction, documented with its immutable policy link in DCC-notes.md.

Summary: DCC associates with caspase-9.

Reason: The assayed partner is caspase-9. Figure 5 uses HA-tagged catalytically inactive caspase-9 in HEK293T co-immunoprecipitation; association decreases with raft disruption or DCC C1121V. The current term requires binding a caspase-family protein, not an active protease or DCC-mediated catalysis. The refinement preserves an experimentally supported association without asserting a purified direct interface or a natural CASP9 splice isoform corresponding to the engineered inactive construct.

Proposed replacements: caspase binding

Summary: DCC associates with the signaling receptor DSCAM in a regulated receptor complex.

Reason: PMID18585357 selected Results report endogenous DCC–DSCAM association in embryonic mouse spinal cord and ligand-dependent complex dissociation. Methods explicitly use rat DCC and mouse DSCAM constructs, consistent with literal mouse Q9ERC8. The evidence supports the receptor partner class; retention of the human curated tuple rests on the established conserved association and curator deference, not a claimed human DCC experiment. Chimeras implicate the transmembrane region, but no purified binary interface was established. GO0005102 does not require demonstration that DCC occupies an agonist site.

Proposed replacements: signaling receptor binding

Summary: Netrin-1 binds a recombinant DCC extracellular fragment.

Reason: PMID19721007 reports binding of netrin-1 to the fourth DCC fibronectin-type III domain in an ELISA. This is positive binding evidence. The inspected ontology results did not establish a suitable binding-to-netrin class: netrin receptor activity adds signal transmission, whereas netrin receptor binding denotes binding to the receptor. Preserve this existing positive generic association as contextual non-core under the user's explicit ClinGen project instruction, documented with its immutable policy link in DCC-notes.md; no signaling assertion is manufactured from binding alone.

Summary: DCC associates with caspase-9 in a netrin-sensitive complex.

Reason: PMID19721007 Figure 3E and the selected Results describe co-immunoprecipitation of myc-DCC and HA-caspase-9 in HEK293T cells. Netrin-1 reduces this association and the DCC fragment perturbation restores it. Caspase-9 is explicitly the assayed partner, supporting caspase binding. The assay establishes association rather than purified binary contact; host-cell identity alone is not used to assign a particular receptor isoform.

Proposed replacements: caspase binding

Summary: DCC retains a netrin-1 association in the local translation study.

Reason: PMID20434207 and its literal spoke-expanded co-immunoprecipitation record support DCC–netrin-1 association. The study connects receptor signaling with translation machinery, but this does not provide a narrower binding-only class for netrin. Preserve the positive existing generic association as contextual non-core; netrin receptor activity remains a separate functional assessment. The user's explicit ClinGen project instruction, documented with its immutable policy link in DCC-notes.md, retains this supported contextual association.

Summary: DCC binds translation machinery, with direct contact demonstrated for RPL5.

Reason: PMID20434207 reports DCC association with 40S, 60S and 80S ribosomal fractions and its cytoplasmic P1-dependent association with translation machinery. Purified recombinant RPL5 binds the DCC cytoplasmic region in a far-Western experiment, providing direct contact evidence distinct from the broader complex assays. Ribosome binding represents the measured source-level function. The term is not being inferred merely because P46777 is a ribosomal protein, and it does not make DCC a structural ribosomal subunit.

Proposed replacements: ribosome binding

Summary: DCC associates with ribosomal complexes containing RPL28.

Reason: PMID20434207 supports DCC–RPL28 coprecipitation and fractionation with ribosomal particles, together with direct source-level evidence that DCC associates with 40S, 60S and 80S fractions. This supports ribosome binding, while the purified binary contact experiment in this paper concerns RPL5, not RPL28. Do not present the three literal RPL28 records as three purified binary assays or infer a large-subunit-only function from the partner name.

Proposed replacements: ribosome binding

Summary: DCC associates with ribosomal complexes containing RPS23.

Reason: PMID20434207 describes DCC association with small and large subunits and 80S particles; the RPS23-associated records are consistent with that source-level ribosome binding. The specific RPS23 evidence is complex association/cosedimentation rather than the purified RPL5 contact assay. Retain this distinction and use the broader measured ribosome-binding function rather than assigning small-subunit specificity solely from P62266 identity.

Proposed replacements: ribosome binding

Summary: The DCC P3 region directly binds the MyTH4–FERM region of myosin-X.

Reason: PMID21642953 uses recombinant human DCC residues 1390–1447 and human MYO10 residues 1486–2058, with an engineered deletion of MYO10 residues 1872–1891 to improve stability. Crystallography and isothermal titration calorimetry support direct binding and the myosin partner class. This is not an assay of an intact motor or full-length membrane receptor. Seven literal database records include mutation-perturbation experiments and must not be described as seven independent wild-type confirmations.

Proposed replacements: myosin binding

Summary: DCC associates with the E3 ubiquitin ligase TRIM9.

Reason: The selected main Results of PMID22084112 explicitly report human TRIM9 interaction with DCC and NEO1 and refer to supplementary Figure S6G. The official Q9C026 record establishes the E3 ligase partner class. Retain the curated positive association and refine to ubiquitin protein ligase binding. The inaccessible supplement leaves the exact human assay and construct details uninspected; most main experiments concern Drosophila, which is not grounds to deny the explicitly reported human result. No claim that DCC is ubiquitinated by TRIM9 follows.

Proposed replacements: ubiquitin protein ligase binding

Summary: Human DCC and netrin-1 show reciprocal extracellular interaction signals in AVEXIS.

Reason: Two literal reciprocal PMID26190107 AVEXIS records identify human P43146 and O95631 and specify DCC 1–1098 and netrin-1 26–459 constructs with assay tags. These provide target-specific support beyond the paper abstract, although the original full Methods remain inaccessible. DCC 1–1098 reaches the first residue of the official predicted transmembrane interval 1098–1122, so it should not be described as exactly the annotated ectodomain 26–1097. Retain the positive generic association as contextual non-core; neither an intact receptor assay nor signaling activity is inferred. The user's explicit ClinGen project instruction, documented with its immutable policy link in DCC-notes.md, retains this supported contextual association.

Summary: The DCC extracellular region binds PSG7 in an extracellular interaction screen and SPR follow-up.

Reason: PMID32822567 Table 1 and selected Results identify PSG7–DCC and confirm it by surface plasmon resonance. The screen and follow-up use recombinant extracellular proteins, including Fc-mediated dimerization that raises avidity. The reported sensorgrams are not monomeric affinity measurements, and physiological DCC signaling by PSG7 was not established. Preserve the experimentally supported generic association as contextual non-core; no narrower performed molecular function is justified. The user's explicit ClinGen project instruction, documented with its immutable policy link in DCC-notes.md, retains this supported contextual association.

Summary: The DCC extracellular region binds IGFBPL1 in a screen and SPR follow-up.

Reason: PMID32822567 explicitly identifies IGFBPL1–DCC in the screen and surface plasmon resonance validation. IGFBP7 is a distinct additional comparison and must not be substituted for literal Q8WX77. Fc-dimerized extracellular constructs support association but do not establish monomeric affinity or physiological receptor signaling. The name insulin-like growth factor-binding protein-like 1 does not make DCC an IGF-binding protein. Retain this positive generic association as contextual non-core. The user's explicit ClinGen project instruction, documented with its immutable policy link in DCC-notes.md, retains this supported contextual association.

Summary: The released distal DCC tail has a modeled cytosolic location.

Reason: The exact Reactome reaction places the released DCC 1291–1447 C-terminal fragment in cytosol. Preserve that processed-product context rather than making intact DCC a soluble cytosolic receptor. The primary intracellular-domain experiments distinguish this inactive tail from the proximal proapoptotic region; they do not directly image native full-length receptor cleavage or tail localization. Retention therefore includes explicit deference to the curated reaction model and its access limits.

Summary: The conserved DCC receptor is located at the plasma membrane.

Reason: PTN008454813 is on the actual human path and carries the plasma-membrane IBD. The specified Dcc and Neo1 donors have positive membrane annotations, while the intact human sequence retains the predicted 1098–1122 transmembrane segment. Independent receptor and membrane-domain experiments support the same location. Multiple source genes here reflect a PAINT ancestral assertion, not a requirement that every donor demonstrate every human experiment.

Summary: The modeled DCC–APPL1–caspase-9 assembly is associated with plasma-membrane DCC.

Reason: The actual R-HSA-373700 input/output complex paths reach human P43146 through a membrane DCC entity. The location is consistent with intact receptor topology and the human membrane-domain experiments. Complex association and functional recruitment are supported; this event does not make DCC an autonomous caspase-9 activator or a protease.

Summary: Mature and membrane-retained processed DCC remain at the plasma membrane.

Reason: The reaction explicitly places mature DCC 26–1447 and the membrane-retained 26–1290 product at the plasma membrane. Both retain the official transmembrane segment; receptor surface and membrane-domain experiments independently support this location. The location supports the performed receptor/signaling functions, without attributing the caspase cleavage reaction to DCC as an enzyme.

Summary: Netrin-induced DCC clustering occurs at the receptor-bearing plasma membrane.

Reason: The actual R-HSA-373707 complexes contain mature DCC 26–1447 at the plasma membrane and resolve to P43146. This is the location of ligand-responsive receptor signaling. The curated clustering model is not treated as an independent measurement of a unique stoichiometry in every cell type.

Summary: The DCC–netrin-1 receptor complex is modeled at the plasma membrane.

Reason: R-HSA-373711 has a literal input/output path to mature human DCC 26–1447 and its plasma-membrane compartment. Binding and receptor experiments independently support membrane-associated netrin reception. The location is retained without turning the pathway summary's proposed domain details into a separate molecular-function assertion.

Summary: DCC is a membrane component of the modeled UNC5–netrin receptor assembly.

Reason: The R-HSA-373713 complex path explicitly includes human P43146 at the plasma membrane. This source describes a context in which DCC cooperates with an UNC5 receptor; it does not establish that every netrin response is repulsive or that DCC alone supplies all repulsive signaling specificity.

Summary: NCK1 recruitment is modeled on plasma-membrane DCC.

Reason: The actual R-HSA-373716 assembly contains membrane DCC and reaches its human reference entity. NCK1 links the receptor to intracellular signaling components. Retaining the receptor location does not ascribe NCK1's SH2/SH3 binding activities to DCC.

Summary: APPL1/DIP13alpha binds the cytoplasmic portion of membrane DCC.

Reason: R-HSA-373717 explicitly places the DCC-containing complex at the plasma membrane and resolves it to P43146. The separately inspected APPL1 original maps an intracellular association. This supports membrane-associated signaling rather than soluble cytosolic localization of the intact receptor.

Summary: The DCC–ezrin complex contains plasma-membrane DCC.

Reason: The R-HSA-374663 input/output paths reach human DCC in the plasma-membrane compartment. The source models association with phosphorylated ezrin; its location supports the receptor context without implying that DCC catalyzes ezrin phosphorylation or independently links every actin component.

Summary: DCC is the membrane-associated target in the SIAH1 regulatory event.

Reason: R-HSA-374665 includes membrane DCC and resolves it to P43146. The cached primary summary describes Siah-dependent regulation of DCC abundance through the ubiquitin–proteasome pathway. DCC is a binding partner and degradation target in this event, not the ubiquitin ligase or the proteolytic enzyme.

Summary: DCC is the membrane-associated target in the SIAH2 regulatory event.

Reason: R-HSA-374667 separately includes membrane DCC in the SIAH2 context and reaches the same human reference sequence. The location is supported independently of the source-specific SIAH paralog. DCC's participation as a regulated substrate does not justify a new ubiquitination or proteolysis activity.

Summary: FYN acts on DCC at the plasma membrane.

Reason: R-HSA-374701 contains both mature DCC and the Tyr1420-phosphorylated DCC entity at the plasma membrane. These entities resolve to human P43146. FYN supplies the kinase activity; DCC is its receptor substrate and signaling partner, so no receptor tyrosine-kinase function is assigned.

Summary: The modeled caspase-activation assembly is organized by membrane-associated DCC.

Reason: R-HSA-418845 reaches human DCC within the membrane-associated activating assembly. The independent 2001 original shows DCC-dependent caspase-9/caspase-3 activation in a cell-extract system requiring additional S100 components. This supports the location and noncatalytic signaling platform, without making DCC the enzyme that processes caspases.

Summary: CDC42 activation is modeled downstream of plasma-membrane DCC.

Reason: The actual R-HSA-418850 catalyst-complex path reaches membrane DCC. A recruited RhoGEF performs nucleotide exchange on CDC42; DCC receives and relays the extracellular signal. The annotation is a supported receptor location, not evidence that DCC itself is a GEF or GTPase.

Summary: RAC1 activation is modeled downstream of plasma-membrane DCC.

Reason: R-HSA-418856 contains DCC within the membrane-associated signaling complex, with a literal path to P43146. DOCK180/TRIO supply the exchange-factor activities in this model. No direct RAC1 exchange activity is transferred to DCC from complex membership.

Summary: Rho-family exchange factors are recruited to membrane DCC assemblies.

Reason: R-HSA-418858 includes the netrin–DCC–NCK1 assembly and its recruited exchange factors at the plasma membrane. The complete typed entity path resolves to human DCC. This is consistent with a receptor signaling platform, while the individual catalytic exchange steps belong to the recruited factors.

Summary: SRC and FYN recruitment occurs in a membrane DCC–FAK signaling assembly.

Reason: The R-HSA-418868 complex path reaches plasma-membrane P43146. FAK and Src-family proteins supply the kinase/scaffold steps described in the reaction. The DCC location is retained without assigning their catalytic activities to the receptor.

Summary: The N-WASP recruitment model contains membrane-associated DCC upstream of actin remodeling.

Reason: R-HSA-418874 reaches DCC through a receptor-associated signaling complex at the plasma membrane. CDC42, NCK1 and N-WASP perform the specified downstream regulatory steps. DCC's modeled membership supports receptor localization, not an autonomous actin-nucleation activity.

Summary: The netrin-4 receptor model places DCC at the plasma membrane.

Reason: R-HSA-593685 explicitly contains human DCC at the plasma membrane. This location is independently secure from netrin-1 receptor and topology evidence, even though netrin-4's context-specific receptor biology is not resolved by this localization row. No new netrin-4 signaling activity or universal ligand assignment is proposed from the model alone.

Summary: DCC performs ligand-absence apoptotic signaling.

Reason: Human DCC expression induces death that netrin-1 suppresses; D1290 mutation and intracellular truncations link the response to the proximal cytoplasmic domain. The current specific pathway definition explicitly includes dependence receptors such as DCC. This refines the existing positive TAS rather than proposing NEW. DCC performs noncatalytic signaling work beyond being a caspase substrate; no autonomous protease activity is implied. Ligand-controlled cleavage of native full-length DCC was not directly demonstrated in the early experiments.

Proposed replacements: extrinsic apoptotic signaling pathway in absence of ligand

Summary: The matching ARBA rule supports the established axon-growth role of DCC.

Reason: Of the 37 actual ARBA00026520 condition sets, branch 15 matches the human protein through all three required FunFam signatures. The rule's axonogenesis conclusion agrees with the independent DCC-dependent outgrowth experiments. This is a verified applicable electronic rule, not a family-name inference; it does not make DCC a structural axon constituent or kinase.

Summary: DCC mediates netrin-responsive axon extension.

Reason: The original rat spinal-explant assays directly establish a DCC-dependent component of netrin-stimulated axon extension, with controls for unrelated outgrowth. The existing human TAS is retained as the established conserved receptor role, with explicit curator deference and rat experimental scope. This source does not supply a direct human-neuron experiment or show antibody blockade of turning inside explants.

Summary: DCC inherits the conserved axon-guidance function of its PAINT clade.

Reason: The actual PTN008454813 IBD is on the human DCC lineage and the target sequence matches the family alignment. Rat Dcc has current experimental guidance evidence tied to PMID8861902; the author chapter confirms receptor binding and axon-outgrowth experiments, with limitations on the particular turning-blockade assay. The ancestral axon-guidance judgment is compatible with the receptor biology. A current IBD also lists a zebrafish source absent from the older seeded WITH/FROM; the original source tuple is preserved and that source-version difference is documented.

Summary: Cell-surface localization is consistent with DCC's inherited receptor architecture.

Reason: The cell-surface IBD at PTN008454813 lies on the actual human path. Its MGI:1097159 source resolves to mouse Neo1/P97798 and retains a current IDA record. The corresponding cached PMID26651291 abstract concerns Neogenin/Lrig2 rather than a direct human DCC assay, and is not used to manufacture such an assay. The PAINT transfer is supported independently by DCC's conserved receptor topology and surface experiments; a related donor does not by itself invalidate the node placement.

Summary: The precise DCC-dependent negative regulation of neuron projection development remains unresolved from the accessible source.

Reason: PMID19616629 explicitly reports that DCC overexpression rescues a phenotype caused by Bcl11A-L knockdown, so this is not a wrong-gene citation. The available abstract combines axon branching, multi-axon formation and dendrite outgrowth without identifying which DCC rescue endpoints support this particular negative-regulation term. The original full Methods/Results were not recovered after bounded publisher and search attempts. Preserve the positive TAS source and leave the precise scope undecided rather than inferring contradiction from the paper's BCL11A emphasis.

Summary: The broad membrane annotation is true but already entailed by the supported plasma-membrane assignments.

Reason: IPR010560 matches residues 1148–1445 of human DCC, and its current mapping plus UniProt SL-0162 supports the generic membrane class. That C-terminal-domain match alone is not a membrane-insertion experiment. Independently accepted plasma-membrane rows already provide a more informative location, so the source is retained as correct but broad; no source term or identifier is rewritten.

Summary: Axonal localization transfers coherently from mouse Dcc to the human guidance receptor.

Reason: The literal mouse P70211 donor has an IDA axon annotation from PMID9331350, whose complete abstract explicitly reports DCC on embryonic mouse retinal ganglion-cell axons and antibody-sensitive netrin responses. A bounded journal-PDF attempt failed, so no uninspected construct or detailed imaging claim is added. The target is the DCC ortholog, not a similarly named paralog, and conserved axonal receptor biology supports the electronic transfer.

Summary: The exact collateral-sprouting claim cannot be resolved from the accessible BCL11A/DCC source.

Reason: The complete PMID19616629 abstract provides positive DCC rescue evidence in a neurite-arborization study, but does not specify the DCC rescue measurement for collateral sprouting. Original full-text access remains unsuccessful. Retain the original TAS assertion without either asserting that every BCL11A endpoint was rescued by DCC or declaring misattribution from the title.

Summary: The deep cell-adhesion inheritance is retained as a contextual receptor-family function.

Reason: PTN002548291 is the actual Eumetazoa root IBD on the human path, not a pairwise transfer from one distant donor. The current specified donors carry positive experimental descendants of cell-cell adhesion, including homophilic, neuronal, calcium-dependent/independent and homotypic adhesion; the exact GO definitions make these is_a children of GO:0098609. An exact same-term-only join would therefore miss valid evidence. DCC retains the extracellular immunoglobulin/fibronectin receptor architecture, and no target-specific loss or contradictory lineage evidence was established. Preserve the broad ancestral judgment without claiming direct human homophilic adhesion or making it a separate core.

Summary: The Schaffer collateral–CA1 synaptic location is a supported rodent-derived context.

Reason: The literal mouse P70211 source retains experimental annotations from PMID23291093. The recovered author's Chapter 3 describes mouse CA3–CA1 Schaffer-collateral electrophysiology and mouse forebrain Dcc deletion, while ultrastructural PSD localization and primary fractionation use adult rat brain. These positive but distinct rodent experiments support the synaptic context and conserved transfer; they are not a direct human synapse image or proof that every DCC pool is postsynaptic.

Summary: Postsynaptic-density membrane localization is retained with its rodent assay context.

Reason: The mouse P70211 donor has current experimental support tied to PMID23291093. In the recovered author chapter, DCC cofractionates with PSD markers and immunoelectron microscopy places it at a subset of adult rat CA1 dendritic-spine PSDs; the mouse experiments separately establish forebrain and spine context. Preserve the human ortholog inference with this species distinction and without claiming a human fractionation assay or uniform localization to every spine.

Summary: DCC supports postsynaptic modulation in the mature hippocampal circuit.

Reason: The actual mouse P70211 donor carries IDA/IMP support from PMID23291093. Its author chapter reports loss of CA3–CA1 LTP after forebrain Dcc deletion in older mice, intact basal transmission/LTD and rescue through enhanced NMDAR function or Src activation. Together with synaptic localization, this supports a performed receptor-signaling contribution rather than a generic necessity-only phenotype. Retain the conserved, context-specific postsynaptic role without treating DCC as an NMDAR channel or Src kinase.

Summary: The DCC-specific negative dendrite-development endpoint remains unresolved.

Reason: PMID19616629 explicitly includes dendrite outgrowth among Bcl11A knockdown phenotypes and states that DCC overexpression rescues a phenotype. The accessible abstract does not establish which dendritic measurements were rescued or the species and exact DCC construct used. The full original was not recovered. Preserve the source and use uncertainty for this precise negative-regulatory assignment; do not equate missing access with evidence that the DCC experiment was absent.