F12 encodes coagulation factor XII, a secreted plasma glycoprotein that circulates as a zymogen. Its activated serine protease, factor XIIa, cleaves factor XI and prekallikrein to generate factor XIa and plasma kallikrein. These reactions connect contact-initiated intrinsic coagulation with the kallikrein-kinin system, in which kallikrein subsequently releases bradykinin from kininogen. Surface association promotes factor XII activation, including autocatalytic amplification and reciprocal activation by kallikrein. The alpha and beta forms arise through proteolytic processing and differ in surface association and substrate responses. Contact reactions occur in extracellular fluid and at external cell surfaces; the activating surface and protein assembly influence whether kallikrein generation is coupled to factor XI activation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002353 plasma kallikrein-kinin cascade | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | ACCEPT | Summary: Activated FXII performs the prekallikrein-activation step of the plasma contact cascade. Reason: The original PMID:18725990 Results and Methods show FXII-dependent conversion of prekallikrein to kallikrein with nonfibrillar protein aggregates and surface controls. Chromozym PK measures the downstream kallikrein, not direct FXII substrate turnover. Independent PMID:34967109 Methods 2.1 and 2.7 explicitly use human FXIIa to activate human prekallikrein, then inhibit FXIIa before measuring generated kallikrein. This is an executed proteolytic step of the cascade, not participation inferred solely from FXII being activated. |
| GO:0002353 plasma kallikrein-kinin cascade | IDA PMID:6793628 Isolation and properties of an abnormal Hageman factor (Fact... | ACCEPT | Summary: Human Hageman factor supplies the active enzyme that initiates prekallikrein activation. Reason: The complete PMID:6793628 original compares purified normal human plasma Hageman factor with the inactive Washington D.C. patient protein. After controlled trypsin activation and blockade of residual trypsin, normal factor generates prekallikrein-activator activity, whereas the abnormal factor does not (Methods, Tables IIβIII and Figures 4β6). These experiments support the cascade role of activated normal FXII; they do not imply that circulating zymogen or every variant is already catalytically active. Supporting Evidence: |
| GO:0002353 plasma kallikrein-kinin cascade | TAS Reactome:R-HSA-9970672 | ACCEPT | Summary: Retain the performed prekallikrein-activation step of the kallikreinβkinin cascade. Reason: The complete R-HSA-9970672 participant graph reaches native human F12 catalysts in the prekallikrein-activation reactions, including R-HSA-9655850 and R-HSA-9909048. This is actual enzyme participation: FXIIa activates prekallikrein, and the resulting kallikrein cleaves kininogen downstream. PMID:34967109 separately assays human FXIIa-dependent prekallikrein activation, with FXIIa inhibition before the kallikrein reporter; PMID:18725990 measures FXII-dependent kallikrein formation with omission controls. Neither downstream reporter is a direct measure of FXII turnover, and F12 is not assigned kininogen-cleaving chemistry. |
| GO:0002542 Factor XII activation | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | ACCEPT | Summary: Surface-dependent FXII autoactivation contributes to FXII activation. Reason: PMID:18725990 describes FXII autoactivation and reciprocal amplification with prekallikrein, but its principal aggregate assay detects downstream kallikrein. Independently, PMID:34967109 Methods 2.5 and Results 3.2 test explicitly human FXII with silica or polyphosphate without adding prekallikrein and quantify generated FXIIa activity using S-2302. Retain the activation role through the documented autoactivation mechanism, while recognizing that kallikrein also activates FXII and that the 2008 mixed assay does not isolate the initiating cleavage. |
| GO:0004252 serine-type endopeptidase activity | EXP PMID:11204562 Factor XII-dependent contact activation on endothelial cells... | ACCEPT | Summary: Processed FXIIa is a serine-type endopeptidase. Reason: The PMID:11204562 abstract reports FXII-dependent contact activation on endothelial proteins, but complete original Methods and reagent details were not recovered. The catalytic function is independently established by normal human plasma FXII activation and active-site labeling in PMID:6793628 and explicit human FXIIa substrate reactions in PMID:34967109. Retain the curatorβs broad enzyme annotation without claiming independent inspection of the inaccessible endothelial experiment or constitutive activity of the zymogen. |
| GO:0004252 serine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the ancestral serine endopeptidase activity. Reason: The PTN001208002 IBD assertion and actual target ancestry are verified. Independent human FXIIa activation of FXI and prekallikrein in PMID:34967109 agrees with internal peptide-bond cleavage and the current EC 3.4.21.38 definition. The functional assays use separate downstream reporters after FXIIa inhibition; they do not establish identical behavior of every processing fragment. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001208002 SUPPORTS TRANSFER The actual PTHR24264 v19 tree and MSA place canonical human P00748 (615 residues, exact sequence match) at PTN002545599 below the asserted node. The recovered IBD and target path contain no relevant NOT assertion. Target self-WITH is valid experimental descendant evidence, not circularity. |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | ACCEPT | Summary: FXIIa catalyzes proteolytic zymogen activation. Reason: PMID:18725990 demonstrates FXII-dependent prekallikrein and, with appropriate surface controls, FXI activation. Its chromogenic readouts detect the generated downstream proteases. Explicit human FXIIa reactions in PMID:34967109 Methods 2.6β2.7 independently establish the enzyme as the performer, while PMID:6793628 supplies active-site and purified human-protein evidence. This supports serine endopeptidase activity of activated FXII rather than direct cleavage of Chromozym PK by FXII in the 2008 assay. |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:6793628 Isolation and properties of an abnormal Hageman factor (Fact... | ACCEPT | Summary: Normal human FXII yields an active serine-protease fragment after activation. Reason: PMID:6793628 reports enzymatic and clotting activity after activation of purified normal human plasma factor, together with diisopropyl fluorophosphate incorporation into the activated approximately 29-kDa fragment. The patient protein is cleaved but lacks corresponding activity and labeling. These positive comparisons support the normal activated enzyme; activation of the preparation by added trypsin is not itself evidence that FXII catalyzes that initial cleavage. Supporting Evidence: |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Retain the specific serine endopeptidase mapping. Reason: Current EC 3.4.21.38 explicitly identifies coagulation factor XIIa and internal ArgβIle substrate cleavage. The official target record contains the trypsin-like catalytic domain and the catalytic relay; human FXIIa activation of FXI and prekallikrein independently supports the activity. Retain the specific enzyme term without treating downstream chromogenic substrate turnover as direct FXII chemistry. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:3.4.21.38 SUPPORTS TRANSFER The current official enzyme entry explicitly identifies factor XIIa and its internal-cleavage chemistry. |
| GO:0004252 serine-type endopeptidase activity | TAS Reactome:R-HSA-9655840 | ACCEPT | Summary: Retain factor XII serine endopeptidase activity in the processing source. Reason: R-HSA-9655840 links catalystActivity 9855680 to the contact complex with explicit activeUnit 158214, human P00748(20β615); the target is not present solely as the processing substrate. The source also represents alpha- to beta-FXIIa processing through the native heavy/light chains. Independent human FXIIa substrate-activation assays support the imported molecular function. This does not independently verify every cleavage assignment or catalyst formulation in the source reaction. |
| GO:0004252 serine-type endopeptidase activity | TAS Reactome:R-HSA-9855735 | ACCEPT | Summary: Retain serine endopeptidase activity in surface-dependent autoactivation. Reason: R-HSA-9855735 explicitly identifies F12 as the catalyst active unit in the polyanion-associated complex. Independently, PMID:34967109 assays human FXII with silica or polyphosphate and zinc without prekallikrein, followed by an FXIIa-calibrated chromogenic readout. This supports surface-dependent autoactivation separately from FXII-dependent kallikrein reporting. The experiment does not map the activation bond or resolve the catalytic contribution of each individual initially single-chain molecule. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Retain predicted calcium binding as a structural-domain facet. Reason: The current InterPro IPR001881 calcium-binding EGF mapping is present in the actual human target at residues 95β131 and 178β210. This is positive domain-based support for calcium binding, rather than an experimentally established F12-specific calcium affinity. The inspected activation and HRG-binding assays emphasize zinc conditions and do not establish calcium binding as a separate principal F12 activity. Retain the predicted structural facet as non-core without confusing calcium with the experimentally manipulated zinc cofactor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR001881 SUPPORTS TRANSFER Actual target matches and the current InterPro2GO calcium-binding mapping are verified; no target-specific calcium-binding experiment was read. Supporting Evidence: GO_REF:0000002 |
| GO:0005515 protein binding | IPI PMID:12011093 A mosquito salivary protein inhibits activation of the plasm... | KEEP AS NON CORE | Summary: FXII and FXIIa bind the mosquito salivary inhibitor hamadarin. Reason: The actual author-hosted JBC Papers-in-Press version of PMID:12011093 reports SPR binding of FXII/FXIIa to immobilized recombinant hamadarin, with blank-flow-cell controls and zinc dependence (SPR Methods and Figures 6β9). Human-plasma contact assays and purchased coagulation proteins are distinguished from a verified current F12 construct sequence. Hamadarin is the inhibitory partner; assigning inhibitor activity to F12 or protease binding on the basis of this nonprotease partner would reverse roles. No supported more specific inhibitor-binding MF was established, so retain this positive generic interaction as non-core. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17645545 Identification and characterization of plasma kallikrein-kin... | KEEP AS NON CORE | Summary: FXII/FXIIa bind triafestin-1 in the contact-system inhibitor experiments. Reason: PMID:17645545 original SPR Methods, Figures 5β9 and Table 1 report binding of FXII and FXIIa to recombinant Triatoma infestans triafestin-1, including the paperβs FXII 1β77 fragment. Purchased plasma proteins, insect-cell inhibitor expression and the fragmentβs paper numbering are retained as separate reagent boundaries; current precursor coordinates were not aligned. The inhibitor suppresses surface association and reciprocal activation, rather than conferring inhibitor activity on F12. A specific inhibitor-binding MF was not established by the term search; the positive generic association is non-core. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17645545 Identification and characterization of plasma kallikrein-kin... | KEEP AS NON CORE | Summary: FXII/FXIIa bind the distinct triafestin-2 inhibitor. Reason: PMID:17645545 Table 1 separately reports FXII, FXIIa and FXII 1β77 interactions with recombinant triafestin-2, supported by the SPR Methods and operative Results. Triafestin-2 is the Ti263 product, distinct from triafestin-1/Ti369; the two-state binding fit is not reduced to an invented simple dissociation constant. This is positive inhibitorβtarget association, not peptidase-inhibitor activity of F12. Retain generic binding as non-core because no justified more specific MF was identified for F12 in this partner role. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17645545 Identification and characterization of plasma kallikrein-kin... | KEEP AS NON CORE | Summary: The FXII N-terminal fragment binds hamadarin in a second original study. Reason: PMID:17645545 Figure 8β9 captions and Table 2 report SPR binding of the paperβs FXII 1β77 fragment to hamadarin, with zinc dependence and a two-state kinetic model. The fragment coordinate is not silently equated to residues 1β77 of the current signal-peptide-containing precursor. PMID:12011093 independently reports FXII/FXIIaβhamadarin binding. The mosquito inhibitorβs activity is not assigned to F12; retain the supported generic binding context as non-core rather than invent an inhibitor-binding specialization. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. |
| GO:0005515 protein binding | IPI PMID:21304106 Histidine-rich glycoprotein binds factor XIIa with high affi... | KEEP AS NON CORE | Summary: Activated Ξ±-FXIIa binds histidine-rich glycoprotein. Reason: The PMID:21304106 abstract positively reports HRG binding to FXIIa, but its full original remains inaccessible. Independent original PMID:34967109 Methods 2.1/2.4 and Results 3.1 use explicitly human Ξ±-FXIIa and human plasma HRG in SPR, with reciprocal immobilization controls. The tested zymogen FXII and Ξ²-FXIIa do not share the Ξ±-FXIIa binding result. This supports the imported interaction without treating all processed forms alike. HRG is the regulator; no specific inhibitor-binding MF for F12 was established, so the binding facet is retained as non-core. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: The neurodegeneration interactome reports an APPβF12 binary-screen interaction. Reason: PMID:32814053 Table S2 (NN1.0) contains the APPβF12 pair, and current IntAct records it in array, prey-pooling and validated two-hybrid contexts. The actual original Methods use human-protein fusion constructs in yeast; the study allows full-length cDNAs or fragments, and the exact F12 insert was not independently sequence-verified. This pair is not an assay of extracellular FXIIa processing or of misfolded AΞ² binding. No specific APP-binding MF or APP-cleavage activity is established for this source, and study-wide orthogonal validation is not assigned to this pair. Retain positive generic binding as non-core. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: The same screen supports an F12βLAMP2 interaction with a literal partner-isoform boundary. Reason: PMID:32814053 Table S2 lists F12βLAMP2, and current IntAct records human P00748βP13473-2 in three two-hybrid method contexts. The -2 suffix belongs to LAMP2, not F12. The original yeast-fusion assay does not establish secretion, proteolytic maturation, endogenous lysosomal activity or the sequence identity of every current natural product. No more specific LAMP2-binding MF was established from this evidence. Retain the source-specific positive pair as non-core, without inferring a lysosomal or autophagic function for FXII. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35817195 Ayaconin, a novel inhibitor of the plasma contact system fro... | UNDECIDED | Summary: AyaconinβFXII binding is positively reported, but its operative assay scope remains unread. Reason: The verified PMID:35817195 abstract reports recombinant sand-fly ayaconin binding to FXII and inhibition when added before FXII activation, with no inhibition of the already activated enzyme. Publisher and author routes did not yield the full Methods, target reagent provenance or binding controls. These are access and attribution limits, not contradictory evidence or a wrong-gene finding. A source-specific decision remains unresolved; neither inhibitor activity nor a more specific binding MF is assigned to F12 from the abstract alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:8710908 Identification of the zinc-dependent endothelial cell bindin... | KEEP AS NON CORE | Summary: FXII binds the endothelial gC1qR/C1QBP protein in a zinc-dependent assay. Reason: Actual original PMID:8710908 Methods and Results, Figures 4β5, report biotinylated FXII binding to HUVEC-purified and recombinant gC1qR, with zinc dependence, metal controls and competition by high-molecular-weight kininogen. The endothelial-cell antibody-blocking experiment measures kininogen binding, not an independently demonstrated FXII cell-binding blockade. C1QBP is a receptor for C1q, not the C1q complement complex itself; complement binding would misidentify the assayed ligand. Retain the positive generic interaction as non-core without assigning an untested receptor or adaptor activity to F12. The standing campaign instruction retains supported generic binding as non-core when no evidence-backed specific molecular function is available; this explicit exception takes precedence over the generic-binding REMOVE default. Supporting Evidence: |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the inherited extracellular pool. Reason: The PTN001208002 extracellular IBD and actual human target ancestry are verified. The mouse F12 donor in PMID:15351846 is independently identified and its plasma protein and functional assays are positive; the human plasma proteins used in PMID:34967109 provide target corroboration. This location covers the circulating and activated extracellular pools without equating all processing forms or predicted transcript products. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001208002 SUPPORTS TRANSFER The actual PTHR24264 v19 tree and MSA place canonical human P00748 (615 residues, exact sequence match) at PTN002545599 below the asserted node. The recovered IBD and target path contain no relevant NOT assertion. Target self-WITH is valid experimental descendant evidence, not circularity. |
| GO:0005576 extracellular region | IDA PMID:6793628 Isolation and properties of an abnormal Hageman factor (Fact... | ACCEPT | Summary: F12 is present as an extracellular plasma protein. Reason: The actual PMID:6793628 Methods purify normal and patient Hageman factor directly from human plasma and compare their activities. This directly establishes the extracellular source, independently of later processing or intracellular biosynthetic transit. The broad extracellular-region annotation is appropriate and does not imply that every protein molecule is activated. Supporting Evidence: |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Retain extracellular location despite an unresolved current ARBA clause. Reason: The exact SL-0243 secreted-location mapping and human plasma-protein experiments support extracellular region. All current ARBA00027128 condition sets were compared with the captured target domain, family and taxonomy fields, but no complete current clause matched. This historical-rule reconstruction gap does not negate independently supported human extracellular location or establish an erroneous original annotation. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB-SubCell:SL-0243 SUPPORTS TRANSFER Current official location maps to extracellular region. ARBA:ARBA00027128 UNRESOLVED No complete current condition set matches the captured target features; the historical trigger is not reconstructed. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-158300 | ACCEPT | Summary: Retain extracellular FXIIa as the factor XI activation catalyst. Reason: R-HSA-158300 catalystActivity 158386 resolves to alpha-FXIIa 158306, containing native human heavy chain 20β372 and light chain 373β615 in the extracellular region. Thus the location belongs to the explicit target enzyme, not merely the platelet-associated factor XI substrate. Human FXIIa-dependent FXI activation is independently assayed in PMID:34967109. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-158313 | ACCEPT | Summary: Retain the extracellular activated-chain products. Reason: R-HSA-158313 processes surface-associated human F12(20β615) to extracellular alpha-FXIIa heavy and light chains. Kallikrein is the activating catalyst in this event; F12 is its substrate, but the target-chain location remains valid. This source-specific location assertion does not transfer kallikrein chemistry to F12 or make proteolytic chains independent natural isoforms. Supporting Evidence: Reactome:R-HSA-158313 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-158357 | ACCEPT | Summary: Retain extracellular alpha-FXIIa in the inhibitor complex. Reason: R-HSA-158357 explicitly contains native human alpha-FXIIa heavy/light chains in the SERPING1-associated extracellular product. F12 is the inhibited enzyme rather than the inhibitor. The participant-level location is supported without inferring that complex formation changes F12 catalytic identity. Supporting Evidence: Reactome:R-HSA-158357 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9651456 | ACCEPT | Summary: Retain native extracellular FXIIa in the disease-partner event. Reason: The disease modification in R-HSA-9651456 belongs to SERPING1. The traced F12 participant is native alpha-FXIIa with unmodified human heavy/light chains in the extracellular region. This is not a disease-F12 location projected onto the normal gene; retain the valid native-target assertion while preserving the failed inhibitor-binding context. Supporting Evidence: Reactome:R-HSA-9651456 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9653249 | KEEP AS NON CORE | Summary: Retain the extracellular disease-variant processing context. Reason: R-HSA-9653249 specifically processes human F12 T328K/R variants by thrombin, producing extracellular 20β328 and 329β615 fragments. The actual modified-residue objects identify P00748 threonine 328 replacement. This is a real F12 disease-product assertion, but not evidence that ordinary F12 undergoes the same processing. Retain the location as a non-core disease context rather than removing a correctly attributed source or treating the fragments as natural isoforms. Supporting Evidence: Reactome:R-HSA-9653249 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9653879 | ACCEPT | Summary: Retain extracellular alpha-FXIIa associated with HRG. Reason: R-HSA-9653879 resolves to native extracellular alpha-FXIIa and HRG. PMID:34967109 independently uses human plasma HRG and human FXII forms in reciprocal surface-plasmon-resonance assays, supporting alpha-FXIIa binding under the tested zinc conditions. Its distinction between alpha-FXIIa, beta-FXIIa and zymogen prevents universalizing this interaction to every processing state. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9655046 | KEEP AS NON CORE | Summary: Retain extracellular products of the variant-specific cleavage pathway. Reason: R-HSA-9655046 describes kallikrein processing of the T328K/R-derived F12 329β615 precursor into a 373β615 light-chain product. The modeled soluble products support extracellular location, but this is a disease-processing context rather than the ordinary gene productβs defining location evidence. The inherited variant annotation records precursor provenance; residue 328 is outside these C-terminal fragments, so it does not mean that the light-chain sequence itself contains that substitution. Supporting Evidence: Reactome:R-HSA-9655046 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9655840 | ACCEPT | Summary: Retain extracellular alpha- and beta-FXIIa chain locations. Reason: R-HSA-9655840 contains native human heavy chain 20β372, light chain 373β615 and the beta-FXIIa heavy-chain fragment 354β362 in the extracellular region. This directly supports the target location while distinguishing processing forms. The particular cleavage sequence and active-unit formulation remain source-model assertions, not newly verified natural-product equivalence. Supporting Evidence: Reactome:R-HSA-9655840 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9655850 | ACCEPT | Summary: Retain extracellular FXIIa during prekallikrein activation. Reason: In R-HSA-9655850, catalystActivity 158386 resolves to native alpha-FXIIa 158306 with its extracellular heavy/light chains. F12 performs the activating proteolysis of prekallikrein; kallikrein then has its own downstream substrates. The human assay in PMID:34967109 independently supports this enzyme role without converting its downstream kallikrein reporter into a direct FXII substrate assay. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9855685 | ACCEPT | Summary: Retain the extracellular F12 pool recruited to a cell-surface complex. Reason: R-HSA-9855685 includes extracellular native P00748(20β615), entity 9855700, before and within assembly with prekallikrein, kininogen and cell-surface receptors. The targetβs extracellular annotation is explicit even when the larger complex is membrane-associated. The assembly event itself is binding, not proof that binding alone activates F12. Supporting Evidence: Reactome:R-HSA-9855685 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9855705 | ACCEPT | Summary: Retain extracellular F12 in polyanion-associated assembly. Reason: R-HSA-9855705 includes native extracellular P00748(20β615) as a free input and in the polyanion-associated product. This source identifies the target compartment rather than inferring it from a generic pathway. Surface-promoted activation is independently tested in PMID:34967109, but complex assembly and catalytic activation remain distinct steps. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9855735 | ACCEPT | Summary: Retain extracellular F12 and FXIIa in autoactivation. Reason: R-HSA-9855735 traces extracellular native F12 through polyanion-associated autoactivation to the native alpha-FXIIa chains. The location applies to the actual target molecules. The isolated no-prekallikrein assay in PMID:34967109 supports functional autoactivation; it does not establish identical behavior of every fragment or proposed transcript model. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9857814 | ACCEPT | Summary: Retain extracellular FXIIa released from a cell-surface activation complex. Reason: R-HSA-9857814 includes native surface-complex F12 and extracellular alpha-FXIIa heavy/light products. The source explicitly assigns F12 as an active unit in this autoactivation model. Retain the location without treating every receptor-binding observation as an autonomous activation assay. Supporting Evidence: Reactome:R-HSA-9857814 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9909046 | ACCEPT | Summary: Retain extracellular FXIIa produced by surface-associated kallikrein. Reason: R-HSA-9909046 processes native F12 in the cell-surface contact complex to extracellular alpha-FXIIa. Its catalyst active unit is KLKB1, not F12. The target location is nevertheless supported; this row does not establish F12 participation as the enzyme in its own kallikrein-dependent activation. Supporting Evidence: Reactome:R-HSA-9909046 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9909048 | ACCEPT | Summary: Retain the extracellular-facing F12 pool in contact activation. Reason: R-HSA-9909048 explicitly contains native human F12 within the surface contact complex and identifies F12 as the active unit for prekallikrein activation. Extracellular localization is compatible with peripheral cell-surface assembly and does not imply a membrane-spanning F12 protein. Human FXIIa-dependent prekallikrein activation independently supports the enzyme role. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9936430 | ACCEPT | Summary: Retain extracellular FXIIa activating the receptor-associated factor XI complex. Reason: R-HSA-9936430 uses the native extracellular alpha-FXIIa catalyst 158306 to activate factor XI in a kininogen/GPIb-associated complex. The target enzymeβs heavy/light-chain compartment is explicit and distinct from the membrane compartment of its substrate complex. PMID:34967109 independently assays FXIIa-dependent FXI activation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9936906 | ACCEPT | Summary: Retain extracellular FXIIa in the aggregate-associated source model. Reason: R-HSA-9936906 resolves to native F12 and alpha-FXIIa chains in an extracellular beta-amyloid/zinc-associated activation model. The location is supported even though aggregate state strongly affects activation. PMID:18725990 reports FXII-dependent kallikrein formation with specified nonfibrillar misfolded preparations and negative tested fibrils; that result must not be generalized to every structure labeled amyloid in a pathway model. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9936909 | ACCEPT | Summary: Retain extracellular native F12 in the amyloid-associated assembly model. Reason: R-HSA-9936909 explicitly includes extracellular native P00748(20β615) and its beta-amyloid/zinc-associated complex. This establishes the source-specific compartment, not universal activation by all amyloid fibrils. The original aggregate experiments in PMID:18725990 distinguish active nonfibrillar preparations from tested inactive fibrils and measure downstream kallikrein formation with FXII/prekallikrein controls. |
| GO:0005791 rough endoplasmic reticulum | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The asserted active rough-ER location exceeds the positive donor residence evidence. Reason: The PTN002545596 IBD and human F12 target descent are verified, and the positive conserved rough-ER residence inference is not rejected. The experimental donor is mouse Hgfac (MGI:1859281/Q9R098), not mouse F12: PMID:12923239 Materials and Methods, Results and Figure 4 caption show antibody-controlled hepatocyte staining and rough-ER immunogold labeling. Its Discussion explicitly states that the antibodies cannot distinguish active from inactive HGFA and interprets the intracellular pool as biosynthetic precursor. These observations do not establish the imported is_active_in relation for human F12. Mark that activity-at-location assertion as over-annotated, while preserving the source fields and positive residence evidence. This does not assert experimentally demonstrated catalytic inactivity, a failed PAINT placement or a direct human F12 imaging result. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002545596 SUPPORTS TRANSFER The actual PTHR24264 v19 tree and MSA place canonical human P00748 (615 residues, exact sequence match) at PTN002545599 below the asserted node. The recovered IBD and target path contain no relevant NOT assertion. MGI:MGI:1859281 SUPPORTS TRANSFER Official mouse Hgfac identity, donor IDA source and actual rough-ER immunogold experiment are verified. They support conserved residence, not the imported is_active_in relation or a target-specific human activity assay. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-158313 | MODIFY | Summary: Specify the external membrane face for receptor-associated native F12. Reason: R-HSA-158313 explicitly inputs native human P00748(20β615), entity 158214, in a cell-surface receptor complex before kallikrein activation. The extracellular receptor-associated protein fits GO:0009897, which includes peripherally attached proteins on the external plasma-membrane side, more precisely than the broad membrane term. This refinement follows the actual source topology; the separately inspected gC1qR ligand-blot work is not treated as intact-cell FXII microscopy. Proposed replacements: external side of plasma membrane Supporting Evidence: Reactome:R-HSA-158313 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9653249 | KEEP AS NON CORE | Summary: Retain the modeled disease-variant membrane-associated pool as contextual. Reason: R-HSA-9653249 inputs T328K/R human F12(20β615) entities 9653238/9653226 at the plasma membrane before thrombin cleavage. The actual residue objects verify the variant identities. Retain this disease-product location without using the specialized processing model as a new principal native-product membrane assertion; native receptor-associated F12 is reviewed separately. This non-core judgment does not imply a wrong gene or a false source compartment. Supporting Evidence: Reactome:R-HSA-9653249 |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: Refine proteolysis to the directly performed zymogen-activation step. Reason: The IPR014394 mapping establishes broad proteolysis, while human FXIIa directly activates inactive FXI and prekallikrein in PMID:34967109. Current GO:0031638 names this proteolytic conversion and is a descendant of proteolysis. F12 performs the activation cleavage of these substrates; it is not merely necessary because another enzyme activates F12. The narrower existing-annotation refinement retains the demonstrated work without adding a redundant NEW process. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR014394 SUPPORTS TRANSFER The valid broad mapping is refined using target-specific performed substrate activation. Proposed replacements: zymogen activation |
| GO:0007596 blood coagulation | IBA GO_REF:0000033 | MODIFY | Summary: Specify the intrinsic coagulation pathway. Reason: The PTN002800021 IBD descends to the human target and is grounded in mouse F12 MGI:1891012. PMID:15351846 directly shows loss of plasma F12 and markedly prolonged aPTT after targeted deletion, while normal bleeding and general health do not negate contact-pathway participation. Independent human FXIIa-dependent FXI activation supplies the performed molecular step. GO:0007597 specifically describes the intrinsic cascade and is a child of blood coagulation, making it more precise than the broad imported term without claiming that F12 is essential for all physiological hemostasis. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002800021 SUPPORTS TRANSFER The actual PTHR24264 v19 tree and MSA place canonical human P00748 (615 residues, exact sequence match) at PTN002545599 below the asserted node. The recovered IBD and target path contain no relevant NOT assertion. Target self-WITH is valid experimental descendant evidence, not circularity. MGI:MGI:1891012 SUPPORTS TRANSFER Actual mouse F12 identity and original plasma/contact-coagulation phenotype support the transfer and its intrinsic-pathway refinement. Proposed replacements: blood coagulation, intrinsic pathway |
| GO:0007597 blood coagulation, intrinsic pathway | IC PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | ACCEPT | Summary: FXIIa executes the initiating FXI-activation step of the intrinsic coagulation pathway. Reason: PMID:18725990 distinguishes misfolded-protein conditions that generate kallikrein without coagulation from dextran-sulfate/surface controls that support FXII-dependent FXI activation and clotting. Thus the negative result for aggregates is not a general denial of intrinsic-pathway participation. Explicit human FXIIaβFXI assays in PMID:34967109 Methods 2.6 and Results 3.6 independently establish the proteolytic step. Preserve the imported IC source context while grounding the biological role in measured chemistry; this does not imply that FXII is indispensable for normal hemostasis. |
| GO:0008233 peptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Specify serine endopeptidase activity rather than broad peptidase activity. Reason: Human FXIIa activation of protein zymogens and current EC 3.4.21.38 establish internal cleavage by the trypsin-like serine protease. GO:0004252 is therefore a supported descendant of peptidase activity. No complete current ARBA00027408 condition matches the captured target features, so historical rule applicability remains unresolved; this does not prevent a specificity refinement supported by independent target chemistry. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00027408 UNRESOLVED All current condition sets were examined; no complete target match was recovered. Independent human target activity supports the specific replacement. Proposed replacements: serine-type endopeptidase activity |
| GO:0010756 positive regulation of plasminogen activation | IDA PMID:89876 Hageman-factor-dependent fibrinolysis: generation of fibrino... | KEEP AS NON CORE | Summary: Activated FXII can promote plasminogen activation through upstream protease activation. Reason: The actual selected original pages of PMID:89876 show Hageman-factor-fragment-dependent activation of prekallikrein and FXI, which then support plasminogen activation and fibrinolysis. At the tested concentrations the fragmentsβ direct plasminogen-activator effect was negligible relative to kallikrein/FXIa. GO:0010756 denotes an increase in the rate, frequency or extent of plasminogen activation; it does not require direct plasminogen cleavage by the regulator. The executed upstream protease activation therefore supports contextual positive regulation, without making FXII the principal direct plasminogen activator or generalizing the assay to all physiological fibrinolysis. The complete paper and figure pixels remain unavailable; actual Methods/Results/caption text on pages 851, 853, 855 and 857 and the Discussion on page 859 were inspected. Supporting Evidence: |
| GO:0016485 protein processing | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | MODIFY | Summary: The measured protein-processing role is specifically zymogen activation. Reason: FXIIa performs proteolytic conversion of prekallikrein and FXI to active enzymes, as shown in PMID:18725990 and in explicitly human reactions in PMID:34967109 Methods 2.6β2.7. GO:0031638 names this precise maturation process and is a current descendant of protein processing, so it is preferable to the broad source term. This refinement concerns F12 doing the cleavage; it does not assign F12 the activity of other enzymes that process the F12 precursor itself. Proposed replacements: zymogen activation |
| GO:0016540 protein autoprocessing | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | ACCEPT | Summary: Surface-dependent FXII autoactivation is supported, with the assay distinction preserved. Reason: The source paper PMID:18725990 describes FXII autoactivation but mainly measures downstream kallikrein in a reciprocal system. Independent PMID:34967109 defines activation by the Arg353βVal354 cleavage in the paperβs mature-protein numbering and tests human FXII with silica/polyphosphate without added prekallikrein, measuring generated FXIIa activity (Methods 2.5; Results 3.2). This supports the established self-processing mechanism. The readout is functional activity, not a newly inspected cleavage-site gel, and it does not make every physiological activation event autocatalytic or resolve which initiating species forms on misfolded aggregates. |
| GO:0030194 positive regulation of blood coagulation | IDA PMID:6793628 Isolation and properties of an abnormal Hageman factor (Fact... | ACCEPT | Summary: Normal activated FXII promotes contact-initiated coagulation. Reason: PMID:6793628 compares clotting correction by purified normal human Hageman factor with the markedly defective patient protein, and relates this to generation of an active protease after cleavage. This supports positive regulation of coagulation in the tested contact pathway. It does not establish an absolute requirement for FXII in normal tissue-factor-driven hemostasis or equivalent activity of the inactive variant. Supporting Evidence: |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | KEEP AS NON CORE | Summary: Human tissue matrix-enriched fractions contain F12 protein. Reason: PMID:25037231 Methods and Additional file 2 provide positive human fraction evidence. Sequential extraction removes cytosolic, nuclear, membrane and cytoskeletal fractions before LC-MS/MS of the insoluble ECM-enriched remainder, with compartment-marker controls. Sheets A/B, row 240, identify F12/P00748 in the ECM-regulator category, with eight total unique peptides and positive detections in normal liver pools and liver metastasis samples; the raw liver extension remains preserved in the source-context record. The historical group P00748|Q8IZZ5|Q96EF3 does not resolve a current product or processed chain. Fraction overlap and plasma carryover are possible limitations, but the inspected source does not demonstrate that the F12 detections are contamination. Retain the positive tissue-localization context as non-core without inferring a structural matrix function. Supporting Evidence: |
| GO:0031638 zymogen activation | IBA GO_REF:0000033 | ACCEPT | Summary: Retain performed activation of protein zymogens. Reason: The actual PTN002800021 IBD for zymogen activation includes human P00748 descendant evidence and lies on the verified target path. Human FXIIa activates FXI and prekallikrein in the separated assays of PMID:34967109; current GO:0031638 describes precisely this proteolytic conversion. F12 is the enzyme for these steps, not merely the substrate of its own activation, and its self-WITH is legitimate experimental grounding. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002800021 SUPPORTS TRANSFER The actual PTHR24264 v19 tree and MSA place canonical human P00748 (615 residues, exact sequence match) at PTN002545599 below the asserted node. The recovered IBD and target path contain no relevant NOT assertion. Target self-WITH is valid experimental descendant evidence, not circularity. |
| GO:0031638 zymogen activation | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | ACCEPT | Summary: FXIIa activates other zymogens by proteolysis. Reason: PMID:18725990 shows FXII-dependent prekallikrein activation and surface-dependent FXI activation, with downstream chromogenic readouts and omission controls. Explicit human FXIIa reactions in PMID:34967109 Methods 2.6β2.7 clarify the performer and substrates. This supports zymogen activation as catalytic work by FXIIa, rather than merely the fact that FXII itself is a zymogen. |
| GO:0031638 zymogen activation | IDA PMID:6793628 Isolation and properties of an abnormal Hageman factor (Fact... | ACCEPT | Summary: Activated normal human FXII converts prekallikrein to an active enzyme. Reason: In PMID:6793628, trypsin-treated purified normal human factor generates prekallikrein-activator activity, while the similarly cleaved abnormal patient factor does not. Residual trypsin is blocked before the downstream assay. The evidence therefore supports FXIIβs role in activating a separate zymogen, without confusing the added trypsinβs initial activation of FXII with FXIIβs own catalytic step. Supporting Evidence: |
| GO:0031638 zymogen activation | IDA PMID:89876 Hageman-factor-dependent fibrinolysis: generation of fibrino... | ACCEPT | Summary: Hageman factor fragments activate prekallikrein and FXI in the reconstructed cascade. Reason: The inspected original PMID:89876 Methods and Results use activated Hageman factor fragments to activate human plasma prekallikrein or FXI; the generated proteases account for downstream fibrinolysis. This is positive zymogen-activation work by the activated F12 product, even though its direct plasminogen-activator contribution is weak under the tested conditions. The sourceβs activated fragment is distinguished from unprocessed precursor and from an inferred splice product. Supporting Evidence: |
| GO:0045087 innate immune response | TAS PMID:2510163 Coagulation factor XII (Hageman factor) Washington D.C.: ina... | UNDECIDED | Summary: The innate-immunity assertion cannot be adjudicated from the accessible variant abstract. Reason: PMID:2510163 is verified as the human Washington D.C. FXII variant study and its abstract describes peptide sequencing and a proposed catalytic defect. The original operative Methods/Results remain inaccessible after bounded PMC, publisher and author-route attempts. The abstract does not provide a test of innate immune participation, but that omission is not grounds to remove the TAS assertion or deny other inflammatory roles of FXII. Retain uncertainty pending the relevant full source and a defined immune step performed by F12. Mutation positions remain the paperβs numbering. Supporting Evidence: |
| GO:0051787 misfolded protein binding | IC PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | KEEP AS NON CORE | Summary: The aggregate-response experiments support inferred recognition of misfolded proteins. Reason: PMID:18725990 compares nonfibrillar misfolded aggregates with native proteins and amyloid fibrils and observes selective FXII-dependent kallikrein generation. The authors infer a shared interaction site; the evidence is a functional activation assay, not a purified binding constant or direct structural interface. The imported IC context is therefore retained as a supported inference and contextual facet. It does not establish an autonomous chaperone, aggregate-clearance activity, or binding to all fibrillar amyloid forms. Supporting Evidence: |
| GO:0051788 response to misfolded protein | IDA PMID:18725990 Misfolded proteins activate factor XII in humans, leading to... | KEEP AS NON CORE | Summary: FXII responds to selected nonfibrillar protein aggregates by initiating the contact cascade. Reason: PMID:18725990 positively demonstrates altered FXII/contact-system activity in aggregate assays and activation markers in systemic-amyloidosis plasma. The tested aggregates stimulate kallikrein generation without the FXI/coagulation response seen with surface controls. Retain this contextual response while keeping the proposed protective clearance role in the Discussion distinct from an experimentally demonstrated function. No general protein-quality-control or clearance process is inferred. Supporting Evidence: |
| GO:0051919 positive regulation of fibrinolysis | IDA PMID:89876 Hageman-factor-dependent fibrinolysis: generation of fibrino... | KEEP AS NON CORE | Summary: FXII can enhance fibrinolysis through the activated contact-system cascade. Reason: The selected original PMID:89876 experiments reconstitute Hageman-factor-dependent fibrinolysis through prekallikrein and FXI pathways, with immunodepletion/reconstitution separating the downstream routes. This supports positive regulation in that biochemical context. It does not establish FXII as the principal fibrin-cleaving enzyme or a major direct plasminogen activator, nor does it define its net effect on fibrinolysis in every physiological setting. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: F12 is detected in a human urine exosome-enriched preparation. Reason: PMID:23533145 Methods, original supplementary protocols and Supplemental Table 2 provide positive human vesicle-enriched fraction evidence. Pooled expressed-prostatic-secretion urine undergoes differential ultracentrifugation and two PBS washes of the final pellet; the preparations contain established exosome-associated markers. Table 2, row 32, identifies P00748/F12 with 8/9 unique peptides in the cancer-pool analyses and 6/5 in the non-cancer-pool analyses. These are replicate analyses of pools, not four independent individuals. The paper discusses soluble/blood-protein carryover and isolation limits, but does not establish target-specific F12 contamination. Retain this reported fraction-associated location as non-core without claiming intravesicular topology, a particular processed chain or an exosome-related molecular function. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which combinations of FXII processing state, surface chemistry and contact cofactors determine whether activation generates kallikrein alone or also activates factor XI under physiological plasma conditions?
Q: What initiates FXII activity in surface-dependent reactions without prekallikrein, and how much is attributable to single-chain FXII activity versus amplification by small amounts of already processed FXIIa?
Experiment: Compare sequence- and chain-verified human FXII, alpha-FXIIa and beta-FXIIa on defined polyphosphate, receptor-bearing endothelial surfaces and characterized nonfibrillar or fibrillar protein preparations. Measure FXI and prekallikrein cleavage separately, quantify the generated proteases after selectively stopping FXIIa, and follow clotting and bradykinin as distinct downstream endpoints. Control zinc, kininogen and active-site concentration, and include FXII-depleted plasma with matched add-back.
Experiment: Reconstitute surface-dependent activation with purified human single-chain FXII and no prekallikrein or other activating protease. Quantify trace processed FXIIa before incubation and follow both chain cleavage and active-site formation over time. Compare catalytic-site and cleavage-resistant variants with wild type, using separately tracked enzyme and substrate preparations and matched surface-free controls. Establish the detection limits for pre-existing FXIIa before assigning initiation to a particular molecular species.
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