BTK is a Tec-family nonreceptor protein tyrosine kinase that couples immune-receptor activation to intracellular signaling. Its PH domain recognizes phosphatidylinositol 3,4,5-trisphosphate and recruits a cytosolic pool to membrane signaling assemblies. In B cells, BTK phosphorylates and activates PLCgamma2 within the BLNK-organized receptor pathway, supporting calcium mobilization, NF-kappaB signaling, activation and differentiation. BTK also phosphorylates substrates in innate immune pathways, including DDX41 and NLRP3, with outputs that depend on cell type and stimulation. SH2/SH3-mediated interactions organize signaling partners, and a smaller pool can shuttle through the nucleus. Loss of functional BTK causes X-linked agammaglobulinemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001780 neutrophil homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BTK helps maintain neutrophil survival and responsiveness. Reason: The rat orthology chain was not traced to its original experiment, but PMID:22366891 independently reports excessive ROS and apoptosis in BTK-deficient human neutrophils, reversed by recombinant BTK. This supports a contextual homeostatic role without assigning BTK a separate lineage-production activity. The exact rat developmental or circulating-cell-count assay is not claimed. |
| GO:0001805 positive regulation of type III hypersensitivity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor source is PMID:22228807, which directly reports suppression of type I and type III hypersensitivity by selective BTK inhibition in rodents and receptor-response inhibition in human cells. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor source is PMID:22228807, which directly reports suppression of type I and type III hypersensitivity by selective BTK inhibition in rodents and receptor-response inhibition in human cells. This supports the conserved contextual immune-response attribution, distinct from BTKβs defining kinase activity; it is pharmacological whole-organism evidence, not a direct mouse genetic dissection of each hypersensitivity subtype. Supporting Evidence: PMID:22228807 effectively preventing type I and type III hypersensitivity responses |
| GO:0001812 positive regulation of type I hypersensitivity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor source is PMID:22228807, which directly reports suppression of type I and type III hypersensitivity by selective BTK inhibition in rodents and receptor-response inhibition in human cells. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor source is PMID:22228807, which directly reports suppression of type I and type III hypersensitivity by selective BTK inhibition in rodents and receptor-response inhibition in human cells. This supports the conserved contextual immune-response attribution, distinct from BTKβs defining kinase activity; it is pharmacological whole-organism evidence, not a direct mouse genetic dissection of each hypersensitivity subtype. Supporting Evidence: PMID:22228807 effectively preventing type I and type III hypersensitivity responses |
| GO:0001818 negative regulation of cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Native mouse Btk-deficient macrophages secrete more TNF-alpha, IL-6 and IL-12p40 after Listeria infection in PMID:23544144. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. Native mouse Btk-deficient macrophages secrete more TNF-alpha, IL-6 and IL-12p40 after Listeria infection in PMID:23544144. This directly supports negative cytokine regulation in that intracellular-infection context, despite BTK promoting inflammatory signaling in other settings. The distinct heat-killed-bacterium and uptake results prevent a universal negative-inflammatory-signaling interpretation. Supporting Evidence: PMID:23544144 Btk (-/-) BMMs showed enhanced TNF-Ξ±, IL-6 and IL-12p40 secretion |
| GO:0002250 adaptive immune response | IBA GO_REF:0000033 | ACCEPT | Summary: BTK contributes centrally to adaptive immunity through antigen-receptor signaling. Reason: The source assertion matches the non-negated adaptive-immune IBD at PTN000700360 and its three exact mouse evidence identifiers. BTK is a nonreceptor tyrosine kinase acting in the B-cell receptor pathway; the independently read biochemical evidence supports that signaling role. No target-specific loss or divergence contradicting this broad ancestral placement was identified. The complete family tree and donor experimental records were not inspected; donor count is not used as a strength score. |
| GO:0002250 adaptive immune response | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BTK is central to adaptive B-cell immunity. Reason: The complete cached review abstract connects BTK to human X-linked agammaglobulinemia and B-cell development, differentiation and receptor signaling. Independent PLCgamma2 biochemical and Ramos-cell evidence supports the pathway contribution, without claiming that every fine-grained assertion in the unavailable full review was read. |
| GO:0002553 histamine secretion by mast cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The traced rat donor experiment is PMID:12220673: Btk siRNA reduces histamine release in RBL-2H3 mast cells, with concordant inhibitor results. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The traced rat donor experiment is PMID:12220673: Btk siRNA reduces histamine release in RBL-2H3 mast cells, with concordant inhibitor results. Native mouse mast-cell receptor-dependent BTK activation and membrane redistribution in PMID:7518558 independently support the conserved signaling context. Retain the secretion attribution as non-core, without relabeling RBL cells as mouse or making BTK the histamine-synthetic enzyme. Supporting Evidence: PMID:12220673 The induction of histamine release, a pro-inflammatory mediator, in RBL-2H3 mast cells was reduced by 20-25% upon Btk down regulation |
| GO:0002639 positive regulation of immunoglobulin production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BTK signaling supports immunoglobulin production through B-cell maturation and activation. Reason: The rat donor assay was not inspected, but the human XLA and B-cell signaling relationship in PMID:19290921 independently supports this regulatory outcome. Retain it as non-core rather than treating BTK as an immunoglobulin synthesis enzyme or asserting a particular donor stimulation protocol. |
| GO:0002721 regulation of B cell cytokine production | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | UNDECIDED | Summary: B-cell cytokine regulation is not resolved by the available review abstract. Reason: The cached PMID:19290921 abstract covers B-cell development, calcium and NF-kappaB signaling but not the particular B-cell cytokine experiment. Full review text and the underlying primary assay were unavailable. General NF-kappaB activation does not verify every downstream cytokine-specific assertion. Supporting Evidence: |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | TAS Reactome:R-HSA-166058 | ACCEPT | Summary: BTK participates in MyD88-dependent Toll-like receptor signaling. Reason: The cached Reactome pathway places BTK in the TIRAP/MyD88 receptor-proximal machinery; the specific human event R-HSA-2201322 describes BTK-dependent TIRAP phosphorylation. This is a direct kinase/signaling contribution, with feedback and cytokine direction depending on cell context. BTK is not assigned the IRAK catalytic reactions elsewhere in the pathway. Supporting Evidence: Reactome:R-HSA-166058 Reactome:R-HSA-2201322 Reactome:R-HSA-2559414 |
| GO:0002902 regulation of B cell apoptotic process | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | KEEP AS NON CORE | Summary: BTK can regulate apoptosis in B-cell signaling contexts. Reason: The cited review abstract does not expose its apoptosis discussion, but PMID:8688094 independently shows a Btk requirement for radiation-induced apoptosis in chicken DT40 cells and rescue by wild-type human BTK. Retain the broad regulatory process as contextual; this experiment does not establish a universal survival-versus-death direction in human B cells. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: A nonreceptor tyrosine-kinase term is more informative than generic protein kinase activity. Reason: The InterPro catalytic-domain inference is correct but broad. BTK is a non-membrane-spanning tyrosine kinase, independently supported by purified substrate-phosphorylation assays and its cytosolic architecture; refine to the existing specific function rather than implying serine/threonine specificity. Proposed replacements: non-membrane spanning protein tyrosine kinase activity |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:11606584 Tyrosine residues in phospholipase Cgamma 2 essential for th... | ACCEPT | Summary: Purified Btk phosphorylates recombinant PLCgamma2. Reason: The cached abstract reports direct phosphorylation and functional PLCgamma2 complementation in chicken DT40 cells. Retrieved primary Methods now identify human BTK constructs purified from Sf9 cells. This resolves the earlier construct-species gap and supports the kinase activity without assigning phospholipase catalysis to BTK. Supporting Evidence: |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:7518558 Tyrosine phosphorylation and activation of Bruton tyrosine k... | ACCEPT | Summary: Btk tyrosine-kinase activity is induced after mast-cell receptor stimulation. Reason: The PMID:7518558 abstract explicitly reports tyrosine phosphorylation and in-vitro kinase activation of Btk after Fc-epsilon-RI cross-linking in mouse bone-marrow-derived mast cells. The mouse context is preserved. Serine/threonine phosphorylation of Btk in that paper describes regulation of the substrate protein, not BTK serine/threonine catalytic specificity. Supporting Evidence: |
| GO:0004713 protein tyrosine kinase activity | IDA PMID:34554188 BTK operates a phospho-tyrosine switch to regulate NLRP3 inf... | ACCEPT | Summary: BTK directly phosphorylates NLRP3 on tyrosine residues. Reason: Inspected PMID:34554188 Results and Methods include purified BTK/NLRP3 assays, wild-type versus kinase-dead K430E controls, inhibitors, and NLRP3 tyrosine-mutant analysis. Human mononuclear-cell observations and mouse macrophage reconstitution are distinguished. This supports BTK catalysis; phosphorylation-site inference from peptides and mutagenesis is not described as complete mass-spectrometric site coverage. Supporting Evidence: |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic tyrosine-kinase mappings agree with direct BTK assays. Reason: The combined catalytic-domain, reaction and orthology evidence is independently corroborated by direct PLCgamma2 and NLRP3 phosphorylation. No audit of every ARBA predicate or donor assay is claimed; the molecular activity itself is established on BTK. |
| GO:0004713 protein tyrosine kinase activity | TAS PMID:11913944 B cell signaling. Introduction. | ACCEPT | Summary: BTK supplies tyrosine-kinase activity in B-cell receptor signaling. Reason: The short PMID:11913944 review abstract places BTK among receptor-proximal kinases. Direct purified-substrate evidence in PMID:11606584 supplies the biochemical anchor missing from a broad introduction. |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-2201322 | ACCEPT | Summary: BTK phosphorylates the Toll adaptor TIRAP. Reason: The specific cached human Reactome event describes TIRAP tyrosine phosphorylation dependent on BTK, including THP-1 inhibitor evidence. The proposed target tyrosines and downstream degradation/feedback model remain event-specific; the reaction supports BTK tyrosine-kinase activity. Supporting Evidence: Reactome:R-HSA-2201322 |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-2424487 | ACCEPT | Summary: BTK participates in PLCgamma phosphorylation in receptor signaling. Reason: The cached reaction describes PLCgamma phosphorylation by BTK/SYK within myeloid receptor machinery. The annotation is BTK kinase activity, not PLCgamma lipase activity. Independent PLCgamma2 phosphorylation in PMID:11606584 corroborates the catalytic class while the reaction-specific PLCgamma1 sites retain their curated context. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: BTK is a non-membrane-spanning protein tyrosine kinase. Reason: The exact IBD at PTN001231474 includes BTK, TEC, BMX and ITK evidence identifiers. Target self-inclusion is legitimate experimental grounding, not circular transfer. The reviewed BTK source has the expected cytosolic kinase architecture and PH-mediated membrane recruitment, without a transmembrane span. The cached PLCgamma2 study reports phosphorylation of recombinant PLCgamma2 by purified Btk; its abstract does not specify the species of that purified construct. This supports the kinase function without inventing a human-only assay. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IDA PMID:11606584 Tyrosine residues in phospholipase Cgamma 2 essential for th... | ACCEPT | Summary: BTK is a non-membrane-spanning PLCgamma2 kinase. Reason: The retrieved human BTK construct and purified-protein experiments support non-membrane spanning protein tyrosine kinase activity. Membrane recruitment through a PH domain does not make BTK a transmembrane receptor; DT40 complementation is a distinct experiment. Supporting Evidence: PMID:11606584 Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IDA PMID:15509800 Mechanism of B-cell receptor-induced phosphorylation and act... | ACCEPT | Summary: BTK catalysis couples BCR engagement to PLCgamma2 activation. Reason: The cached abstract reports Btk-dependent PLCgamma2 Tyr753/Tyr759 phosphorylation and phospholipase activity in human Ramos cells and murine splenic B cells, using depletion and inhibitors. Tyr1217 follows a different dependence. These results support the established nonreceptor tyrosine-kinase activity without treating all PLCgamma2 phosphosites as BTK-specific. Supporting Evidence: |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 2.7.10.2 correctly identifies BTK nonreceptor tyrosine-kinase activity. Reason: The enzyme-class mapping agrees with the protein architecture and direct purified-substrate phosphorylation. It is a valid electronic annotation independently supported by experiment. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IGI PMID:14656219 Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylat... | ACCEPT | Summary: BTK tyrosine-kinase activity contributes to platelet PLCgamma2 signaling. Reason: The complete PMID:14656219 abstract distinguishes GPVI and GPIb-IX-V signaling and reports Btk phosphorylation of PLCgamma2-derived peptides. The IGI partner P16885 is retained. This supports the catalytic class but does not establish a purified stable BTKβPLCG2 binding complex in that source. Supporting Evidence: |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BTK is a cytoplasmic Tec-family tyrosine kinase. Reason: This molecular identity is explicit in the complete review abstract and is independently demonstrated by the biochemical PLCgamma2 and NLRP3 studies. PH-mediated recruitment to a membrane is compatible with a non-membrane-spanning kinase. |
| GO:0005515 protein binding | IPI PMID:11788586 Interaction of Bruton's tyrosine kinase and protein kinase C... | MODIFY | Summary: BTK associates with PKC-theta in stimulated platelets. Reason: PMID:11788586 explicitly reports physical association of BTK and PKC-theta during platelet activation. The partner Q04759 is PKC-theta, making protein kinase C binding a supported refinement. This binding judgment does not require BTK to catalyse phosphorylation of PKC-theta or assert purified binary binding. Proposed replacements: protein kinase C binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:15046600 Btk-dependent regulation of phosphoinositide synthesis. | UNDECIDED | Summary: The exact PIKFYVE partner mapping remains unresolved. Reason: The PMID:15046600 abstract describes BTK-associated PIP5Ks that produce phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate. The source partner Q9Y2I7 instead identifies PIKFYVE, a phosphatidylinositol 3-phosphate 5-kinase. The accessible abstract does not establish this exact partner assertion, and its full target assay was not inspected. Preserve the accession and uncertainty; neither silently relabel it as a PIP5K isoform nor reject the experimental annotation from abstract emphasis alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:15539407 Regulated association of protein kinase B/Akt with breast tu... | UNDECIDED | Summary: The exact BTKβPTK6 interaction was not recovered from accessible source text. Reason: PMID:15539407 describes BRK/PTK6 and Akt association in its abstract, while the GOA partner here is PTK6/Q13882. The BTK target-specific assay was not available for inspection. A paper foregrounding BRK does not establish that BTK was not also assayed; retain the source fields and uncertainty. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16969585 Solution structure and phosphopeptide binding of the SH2 dom... | REMOVE | Summary: Remove uninformative bare protein binding while preserving the reported interaction. Reason: The journal cache for PMID:16969585 contains citation metadata but no substantive abstract. The primary author's 2006 doctoral abstract independently describes structural work on the human BTK SH2 domain and binding to a human BLNK phosphopeptide. Together with the curated source assertion, this supports retaining BTKβBLNK binding as non-core. This is claim-level corroboration, not verification of every experiment in the original journal article; a finer phosphopeptide-binding term is not proposed from the inaccessible journal assay. The earlier task-specific ClinGen retention instruction is superseded for this module audit by the current protein-binding policy. Remove only the uninformative GO:0005515 label; the documented partner association and assay limits remain intact, and no reversed-domain or unsupported activity replacement is proposed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19214191 Signalling of the BCR is regulated by a lipid rafts-localise... | MODIFY | Summary: BTK associates with the DNA-binding transcription factor TFII-I. Reason: PMID:19214191 describes the BrightβBTKβTFII-I assembly and identifies TFII-I/GTF2I as a DNA-binding transcription factor, consistent with source partner P78347. DNA-binding transcription factor binding refines the physical association without assigning transcription-factor activity to BTK. The complex has both nuclear and membrane-associated contexts; the annotation does not assert purified direct binary binding. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19214191 Signalling of the BCR is regulated by a lipid rafts-localise... | MODIFY | Summary: BTK associates with the DNA-binding transcription factor Bright/ARID3A. Reason: PMID:19214191 identifies Bright/ARID3A as a DNA-binding transcription factor and reports its association with BTK in B-cell complexes, including the human Daudi/Raji raft experiments. The Q99856 partner supports refinement to DNA-binding transcription factor binding. This does not transfer Bright's own DNA-binding or transcriptional activity to BTK, and complex association is distinguished from purified binary binding. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22366891 The kinase Btk negatively regulates the production of reacti... | UNDECIDED | Summary: The exact MAL accession behind this interaction needs resolution. Reason: PMID:22366891 describes BTK-dependent confinement of the Toll-signalling adaptor called Mal. The machine source partner is P21145 (MAL), and the inspected abstract does not resolve that accession against the adaptor Mal/TIRAP nomenclature. Do not silently substitute another partner or pronounce a mapping error without the original reagents and assay record. Retain the assertion as unresolved. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: Remove uninformative bare protein binding (HSP90AB1 interaction survey edge). Reason: Bare protein binding (GO:0005515) carries no functional information and is removed per the protein-binding policy; PMID:22939624 is a readable HSP90 interaction survey (partner HSP90AB1/P08238), so the term is uninformative rather than undecidable, and removal does not deny the interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25825872 Preferred SH3 domain partners of ADAM metalloproteases inclu... | REMOVE | Summary: Remove uninformative bare protein binding while preserving the reported interaction. Reason: PMID:25825872 explicitly reports ADAM15 binding to BTK in the SH3 interaction analysis. The inspected Methods describe GST-BTK SH3 peptide-array assays; these support a bounded physical interaction with Q13444. The paper's full-length cellular validation of other ADAM partners is not treated as a BTKβADAM15 cellular experiment, and ADAM15 protease activity is not transferred to BTK. The earlier task-specific ClinGen retention instruction is superseded for this module audit by the current protein-binding policy. Remove only the uninformative GO:0005515 label; the documented partner association and assay limits remain intact, and no reversed-domain or unsupported activity replacement is proposed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Remove uninformative bare protein binding (MEOX2 interaction survey edge). Reason: Bare protein binding (GO:0005515) carries no functional information and is removed per the protein-binding policy; PMID:25910212 is a readable transcription-factor interaction survey (partner MEOX2/P50222), so the term is uninformative rather than undecidable. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Remove uninformative bare protein binding (KATNB1 affinity-purification edge). Reason: Bare protein binding (GO:0005515) carries no functional information and is removed per the protein-binding policy; PMID:28514442 is a readable affinity-purification interaction study (partner KATNB1/Q9BVA0), so the term is uninformative rather than undecidable. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Remove uninformative bare protein binding (HSP90AB1 interaction-map edge). Reason: Bare protein binding (GO:0005515) carries no functional information and is removed per the protein-binding policy; PMID:33961781 is a readable proteome-scale interaction map (partner HSP90AB1/P08238), so the term is uninformative rather than undecidable. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Remove uninformative bare protein binding (KATNB1 interaction-map edge). Reason: Bare protein binding (GO:0005515) carries no functional information and is removed per the protein-binding policy; PMID:33961781 is a readable proteome-scale interaction map (partner KATNB1/Q9BVA0), so the term is uninformative rather than undecidable. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:8892607 Evidence that the Wiskott-Aldrich syndrome protein may be in... | REMOVE | Summary: Remove uninformative bare protein binding while preserving the reported interaction. Reason: The PMID:8892607 abstract explicitly includes BTK among the SH3-containing proteins that bind WASP. Retain the P42768 interaction as non-core. Here BTK supplies the SH3 domain, so converting the assertion to SH3-domain binding would reverse the experimentally described direction; WASP actin-regulatory activity is not a BTK function. The earlier task-specific ClinGen retention instruction is superseded for this module audit by the current protein-binding policy. Remove only the uninformative GO:0005515 label; the documented partner association and assay limits remain intact, and no reversed-domain or unsupported activity replacement is proposed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:9012831 BAP-135, a target for Bruton's tyrosine kinase in response t... | MODIFY | Summary: BTK associates with BAP135/TFII-I, a DNA-binding transcription factor. Reason: PMID:9012831 reports endogenous BTKβBAP135 association in human Ramos cells and reciprocal association after expression. PMID:19214191 identifies BAP135/TFII-I as the DNA-binding transcription factor GTF2I, matching P78347 and supporting DNA-binding transcription factor binding. The earlier in-vitro domain constructs used murine Btk; the human endogenous association is separately supported. Neither the binding result nor phosphorylation association alone establishes direct in-vivo BTK substrate catalysis. Proposed replacements: DNA-binding transcription factor binding |
| GO:0005515 protein binding | IPI PMID:9571151 Identification and characterization of a novel SH3-domain bi... | REMOVE | Summary: Remove uninformative bare protein binding while preserving the reported interaction. Reason: The PMID:9571151 abstract describes interaction cloning and immunoprecipitation identifying Sab/SH3BP5 as a BTK partner. Retain the O60239 association. BTK is the SH3-domain-containing binding partner, so SH3-domain binding would reverse this interaction; Sab's effects on BTK activity are not assigned as BTK's own inhibitory activity. The earlier task-specific ClinGen retention instruction is superseded for this module audit by the current protein-binding policy. Remove only the uninformative GO:0005515 label; the documented partner association and assay limits remain intact, and no reversed-domain or unsupported activity replacement is proposed. Supporting Evidence: |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: BTK binds ATP as the phosphate donor for kinase catalysis. Reason: The kinase-domain inference agrees with the reviewed ATP-binding region and ATP-dependent purified kinase assays. This is a necessary part of the kinase mechanism, not an additional independent core activity. |
| GO:0005524 ATP binding | TAS PMID:11913944 B cell signaling. Introduction. | ACCEPT | Summary: ATP binding is part of BTK tyrosine-kinase catalysis. Reason: The short B-cell-signaling review is a broad source, while direct ATP-dependent BTK substrate-phosphorylation assays independently support this molecular requirement. No ATPase activity is inferred. |
| GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding | IDA PMID:17823121 Mechanistic basis of differential cellular responses of phos... | ACCEPT | Summary: The BTK PH domain selectively recognizes PIP3. Reason: The complete PMID:17823121 abstract reports surface-plasmon-resonance and monolayer analyses that distinguish Btk-PH PIP3 specificity from other PH domains, alongside reversible recruitment in stimulated NIH 3T3 cells. This directly supports lipid recognition; isolated-domain experiments do not establish universal endogenous membrane occupancy or every alternative-product behavior. Supporting Evidence: |
| GO:0005634 nucleus | EXP PMID:11016936 Nucleocytoplasmic shuttling of Bruton's tyrosine kinase. | KEEP AS NON CORE | Summary: Wild-type BTK can shuttle through the nucleus. Reason: The complete PMID:11016936 abstract reports nuclear localization of both endogenous and ectopic Btk and CRM1-sensitive export. Domain deletions accentuate nuclear accumulation but are not the sole evidence for the wild-type location. Retain as a contextual location rather than make nuclear activity the main kinase location. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The nuclear mapping is compatible with experimentally observed BTK shuttling. Reason: The source combines mouse orthology and a UniProt location mapping. Independent endogenous and ectopic Btk observations support nuclear access; this does not imply constitutive nuclear enrichment or identical localization of every product. |
| GO:0005634 nucleus | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | KEEP AS NON CORE | Summary: Nuclear access is a supported secondary BTK localization. Reason: The full review discussion is unavailable, but the independently cached nucleocytoplasmic-shuttling abstract establishes wild-type nuclear access and export. The review citation is retained without claiming its uninspected details. |
| GO:0005737 cytoplasm | EXP PMID:11016936 Nucleocytoplasmic shuttling of Bruton's tyrosine kinase. | ACCEPT | Summary: BTK occupies the cytoplasm and undergoes regulated shuttling. Reason: The source directly describes cytoplasmic wild-type Btk, with regulated nuclear export and redistribution. This is compatible with stimulus-dependent membrane recruitment and occasional nuclear localization. Supporting Evidence: |
| GO:0005737 cytoplasm | EXP PMID:25704810 Bruton's tyrosine kinase phosphorylates DDX41 and activates ... | ACCEPT | Summary: BTK operates in cytoplasmic innate immune signaling. Reason: The complete PMID:25704810 abstract describes interactions with the cytosolic DNA sensor DDX41 and STING-associated machinery, including kinase-dependent phosphorylation. This is consistent with cytoplasmic BTK; exact subcellular microscopy and construct conditions from the full paper were not accessible. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:17823121 Mechanistic basis of differential cellular responses of phos... | ACCEPT | Summary: The resting BTK PH-domain reporter is cytoplasmic before membrane recruitment. Reason: The source compares isolated PH-domain membrane-binding properties and reversible recruitment in NIH 3T3 cells. Its construct scope is explicit; independent full-length BTK redistribution in PMID:10602036 supports the broader protein localization. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic cytoplasmic annotation agrees with direct localization. Reason: The mouse/subcellular-location mapping is independently corroborated by wild-type BTK shuttling and full-length GFP-BTK redistribution studies. No constitutive exclusive localization is implied. |
| GO:0005737 cytoplasm | TAS PMID:15046600 Btk-dependent regulation of phosphoinositide synthesis. | ACCEPT | Summary: Cytoplasmic BTK is recruited into membrane signaling assemblies. Reason: The PMID:15046600 abstract describes transport of associated phosphoinositide-kinase machinery to the plasma membrane and lipid rafts during BTK signaling. Independent full-length localization experiments corroborate the cytoplasmic pool; the unresolved source partner accession in the separate binding row is not silently resolved. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: A cytosolic BTK pool is independently supported. Reason: The exact Human Protein Atlas imaging record was not inspected, but independent endogenous shuttling and full-length redistribution experiments establish this compartment. Retain the curator location without claiming the specific antibody or cell line in this source. |
| GO:0005829 cytosol | IDA PMID:17823121 Mechanistic basis of differential cellular responses of phos... | ACCEPT | Summary: BTK PH-domain experiments are compatible with a soluble cytosolic pool. Reason: The PH-domain reporter is recruited reversibly from the cell interior to PIP3-containing membranes; full-length BTK localization independently corroborates a cytosolic pool. The isolated-domain data are not described as endogenous whole-protein microscopy. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA cytosol prediction agrees with direct BTK localization. Reason: Cytosolic residence and regulated membrane recruitment are experimentally supported. The molecular location is accepted without claiming a new reconstruction of the ARBA rule. |
| GO:0005829 cytosol | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BTK is a cytosolic signaling kinase. Reason: The review abstract explicitly identifies BTK as a cytoplasmic kinase; primary redistribution and shuttling studies corroborate the soluble cytosolic pool and its regulated relocalization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns MyD88 recruitment to activated TLRβTIRAP. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK4 recruitment. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166091 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK1/IRAK2 recruitment. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166119 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns the first IRAK1 phosphorylation step. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns the second IRAK1 phosphorylation step. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166286 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK1 hyperphosphorylation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166362 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK1βTRAF6 release. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166363 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns TRAF6 recruitment. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2201322 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns BTK-dependent TIRAP phosphorylation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2262775 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK2βTRAF6 release. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2262777 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK2βTRAF6 association. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424476 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns VAV-mediated RAC activation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424481 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns SLP-76 recruitment of VAV and BTK. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424484 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns SYK-dependent BTK activation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424485 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns PLCgamma1 release and lipid hydrolysis. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424486 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns VAV activation by upstream kinases. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424487 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns PLCgamma phosphorylation by BTK/SYK. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2559414 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns BTK recruitment to activated TLR2/4βTIRAP. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730833 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns TEC-family kinase recruitment and phosphorylation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730847 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns PLCG-mediated PIP2 hydrolysis. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730858 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns BTK/ITK autophosphorylation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns defective IRAK4 recruitment. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602383 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns defective MyD88 oligomerization. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602606 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns defective MyD88βTIRAP binding. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964241 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns PIP3/G-beta-gamma-dependent BTK recruitment. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964246 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns BTK activation in a G-alpha-12 complex. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964271 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns G-beta-gamma-dependent BTK activation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964274 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns G-alpha-12 association with BTK. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964280 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns active Gq association with BTK. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964284 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns Gq-dependent release of BTK autoinhibition. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964317 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns release of active BTK from a G-beta-gamma complex. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964333 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns release of active BTK from a G-alpha-12 complex. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8964340 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns release of active BTK from a Gq complex. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937022 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK4 autophosphorylation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937059 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns IRAK2 phosphorylation. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns Myddosome assembly. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9606151 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns phosphorylated BLNK recruitment of BTK and PLCgamma2. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9691421 | ACCEPT | Summary: The cytosolic BTK location is compatible with the curated signaling event. Reason: The cached Reactome event concerns binding of inhibitors to BTK. Its cytosolic BTK compartment agrees with independent localization and recruitment experiments. This row asserts location, not that BTK catalyses every reaction described in the event or remains a permanent subunit of each intermediate complex. |
| GO:0005886 plasma membrane | EXP PMID:10196179 Phosphatidylinositol 3-kinase-dependent membrane association... | MODIFY | Summary: The BTK PH domain mediates inducible plasma-membrane recruitment. Reason: PMID:10196179 directly describes PH-domain GFP recruitment in NIH 3T3 cells following EGF/PDGF stimulation, dependence on PI3K and inhibition by the R28C mutation. Full-length BTK redistribution is independently reported in PMID:10602036. Recruitment is peripheral and regulated, not a transmembrane topology. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane |
| GO:0005886 plasma membrane | EXP PMID:10602036 Redistribution of Bruton's tyrosine kinase by activation of ... | MODIFY | Summary: Full-length BTK relocates to the plasma membrane in response to upstream signals. Reason: The cached abstract reports PI3K- and Rho-family-dependent redistribution of Btk-GFP, including wild-type as well as gain-of-function forms. The DT40 cytoskeletal findings and NIH 3T3 localization experiments are kept distinct. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MODIFY | Summary: Activated BTK is recruited to and functions at the plasma membrane. Reason: The exact plasma-membrane IBD and complete seed set at PTN002521457 match this source row. A broad ancestral node and multiple donor proteins do not make the localization false for BTK. Independent cached studies report PI3K-dependent recruitment of BTK PH-domain GFP or BTK-GFP constructs to the membrane. Resting cytosolic localization is compatible with transient membrane activity. Those abstracts were read, but their figures and complete methods were not; the full ancestral tree was not reconstructed. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Propagation Review Root cause: TERM SCOPING PROBLEM Proposed replacements: cytoplasmic side of plasma membrane |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | MODIFY | Summary: Plasma-membrane recruitment is independently established. Reason: The exact HPA immunofluorescence image was not inspected. However, direct full-length BTK and PH-domain localization studies support stimulus-dependent membrane recruitment, so lack of access to this particular image does not overturn the correct compartment assertion. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane |
| GO:0005886 plasma membrane | IDA PMID:17823121 Mechanistic basis of differential cellular responses of phos... | MODIFY | Summary: PIP3 binding recruits the BTK PH domain to the plasma membrane. Reason: The quantitative lipid-binding and NIH 3T3 translocation experiments in the abstract support this location at the construct level. Independent full-length BTK redistribution corroborates its relevance to the native protein. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | MODIFY | Summary: The mapped plasma-membrane location agrees with direct recruitment assays. Reason: UniProt location mapping is consistent with the PH-dependent peripheral membrane recruitment demonstrated experimentally. BTK remains a nonreceptor kinase rather than an integral membrane protein. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane |
| GO:0005886 plasma membrane | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | MODIFY | Summary: Membrane recruitment is part of BTK activation. Reason: The review emphasizes the PH domain and its regulation, while direct primary localization evidence verifies stimulus-dependent plasma-membrane association. No constitutive membrane residence is claimed. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1112666 | MODIFY | Summary: BTK acts at the membrane-associated BLNKβPLCgamma2 signalosome. Reason: The Reactome event places BTK in the BCR signaling assembly that activates PLCgamma2 near its membrane substrate. The location is supported; the phosphatidylinositol hydrolysis named by the event is performed by PLCgamma2, not BTK. The more specific supported term is cytoplasmic side of plasma membrane (GO:0009898), supported by the inner-leaflet anchoring/recruitment evidence though not yet a separate GOA row -- the protein is lipid-anchored or recruited to the inner (cytoplasmic) leaflet and faces the cytosol, not the cell exterior. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: Reactome:R-HSA-1112666 |
| GO:0007498 mesoderm development | TAS PMID:8013627 An exon-skipping mutation in the btk gene of a patient with ... | UNDECIDED | Summary: The mesoderm-development claim remains unverified. Reason: The PMID:8013627 abstract describes an exon-skipping BTK mutation in a patient with XLA and isolated growth-hormone deficiency; it does not expose a mesoderm-development experiment. Full relevant evidence was unavailable. The clinical association neither establishes this embryological process nor proves that the curator cited the wrong gene. Supporting Evidence: |
| GO:0016004 phospholipase activator activity | IDA PMID:11606584 Tyrosine residues in phospholipase Cgamma 2 essential for th... | MODIFY | Summary: The demonstrated activation mechanism is BTK tyrosine-kinase catalysis. Reason: GO:0016004 descends through enzyme activator activity from molecular function regulator activity, whose definition excludes regulation by covalent modification. PMID:11606584 establishes phosphorylation of PLCgamma2 by purified human BTK. Refine this mechanistic assertion to non-membrane spanning protein tyrosine kinase activity, already independently represented in the review. This does not infer a separate noncovalent phospholipase-activator mechanism or transfer PLCgamma2 lipid hydrolysis to BTK. Proposed replacements: non-membrane spanning protein tyrosine kinase activity Supporting Evidence: |
| GO:0018108 peptidyl-tyrosine phosphorylation | IDA PMID:11606584 Tyrosine residues in phospholipase Cgamma 2 essential for th... | ACCEPT | Summary: BTK catalyses phosphorylation of protein tyrosine residues. Reason: Direct purified Btk phosphorylation of recombinant PLCgamma2 and tyrosine-containing peptides establishes participation by BTK itself. PLCgamma2 is the substrate, and the functional DT40 rescue experiments complement rather than replace this catalytic evidence. Supporting Evidence: |
| GO:0019722 calcium-mediated signaling | TAS PMID:15046600 Btk-dependent regulation of phosphoinositide synthesis. | ACCEPT | Summary: BTK couples receptor signaling to calcium mobilization. Reason: The source describes BTK-dependent phosphoinositide supply and PLCgamma2 signaling. Independent PLCgamma2 phosphosite rescue and Ramos-cell activation studies establish how BTK contributes to the calcium-generating pathway. BTK is the regulatory kinase, whereas PLCgamma2 generates the lipid-derived second messengers. |
| GO:0030167 proteoglycan catabolic process | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat donor trace resolves proteoglycan catabolism to PMID:32083858, a remibrutinib discovery/arthritis study. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor trace resolves proteoglycan catabolism to PMID:32083858, a remibrutinib discovery/arthritis study. Its accessible abstract reports dose-dependent arthritis efficacy but does not resolve a BTK-executed catabolic step versus altered inflammatory matrix destruction. The full assay context remains inaccessible; do not infer direct proteoglycan degradation from inhibitor efficacy or assert that the donor experiment is false. Supporting Evidence: |
| GO:0030890 positive regulation of B cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Full rat donor PMID:28352114 shows reduced activated splenic-cell proliferation after treatment in arthritic animals, but no significant inhibition of LPS-stimulated normal rat B-cell proliferation in the isolated assay (Fig.4). Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. Full rat donor PMID:28352114 shows reduced activated splenic-cell proliferation after treatment in arthritic animals, but no significant inhibition of LPS-stimulated normal rat B-cell proliferation in the isolated assay (Fig.4). Retain a disease-context positive regulatory attribution with that boundary, not a universal requirement for all B-cell proliferation or a direct mouse proliferation measurement. Supporting Evidence: PMID:28352114 neither CHMFL-BTK-11 nor PCI-32765 had significant anti-proliferation efficacy against activated B-cells |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000107 | UNDECIDED | Summary: The original PMID:14657254 cache explicitly concerns adrenal hormone-sensitive lipase and cholesterol handling. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The original PMID:14657254 cache explicitly concerns adrenal hormone-sensitive lipase and cholesterol handling. Normal retrieval did not recover the full article or the BTK-specific vesicle-localization experiment. Cytosolic BTK and membrane recruitment do not resolve this particular vesicle assertion; retain uncertainty rather than infer a wrong-gene citation from the abstract. Supporting Evidence: |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor source PMID:28352114 and native mouse infection studies support context-dependent BTK participation in inflammatory responses. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor source PMID:28352114 and native mouse infection studies support context-dependent BTK participation in inflammatory responses. The former also tests LPS-stimulated human PBMC cytokines. Response to LPS is retained as a broad stimulus context, not a claim that all downstream responses have the same sign or that every assay directly tested mouse BTK. |
| GO:0032693 negative regulation of interleukin-10 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor source PMID:28352114 supports negative IL-10 regulation in a systemic arthritis/drug-treatment setting, with cytokine-specific effects rather than uniform inflammatory suppression. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor source PMID:28352114 supports negative IL-10 regulation in a systemic arthritis/drug-treatment setting, with cytokine-specific effects rather than uniform inflammatory suppression. Retain the transferred regulatory claim as contextual; TNF changes in the rat systemic assay are small, whereas the paper also demonstrates inhibited LPS-triggered TNF in human PBMCs. These are not direct mouse cytokine assays or evidence that BTK itself synthesizes cytokines. Supporting Evidence: PMID:28352114 enhanced the production of IL-10 |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor source PMID:28352114 supports positive IL-6 regulation in a systemic arthritis/drug-treatment setting, with cytokine-specific effects rather than uniform inflammatory suppression. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor source PMID:28352114 supports positive IL-6 regulation in a systemic arthritis/drug-treatment setting, with cytokine-specific effects rather than uniform inflammatory suppression. Retain the transferred regulatory claim as contextual; TNF changes in the rat systemic assay are small, whereas the paper also demonstrates inhibited LPS-triggered TNF in human PBMCs. These are not direct mouse cytokine assays or evidence that BTK itself synthesizes cytokines. Supporting Evidence: PMID:28352114 reduced the production of IL-6 |
| GO:0032760 positive regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor source PMID:28352114 supports positive TNF regulation in a systemic arthritis/drug-treatment setting, with cytokine-specific effects rather than uniform inflammatory suppression. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor source PMID:28352114 supports positive TNF regulation in a systemic arthritis/drug-treatment setting, with cytokine-specific effects rather than uniform inflammatory suppression. Retain the transferred regulatory claim as contextual; TNF changes in the rat systemic assay are small, whereas the paper also demonstrates inhibited LPS-triggered TNF in human PBMCs. These are not direct mouse cytokine assays or evidence that BTK itself synthesizes cytokines. Supporting Evidence: PMID:28352114 TNF-Ξ± and IL-17A was slightly affected |
| GO:0034614 cellular response to reactive oxygen species | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The traced rat source PMID:10744701 demonstrates BTK activation by fungal spores dependent on endogenous reactive oxygen production. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The traced rat source PMID:10744701 demonstrates BTK activation by fungal spores dependent on endogenous reactive oxygen production. It specifically reports that exogenous hydrogen peroxide alone activated SYK, not the same set of kinases. Retain a contextual endogenous-ROS response inference rather than generalizing BTK activation to every oxidant treatment. Supporting Evidence: PMID:10744701 endogenous reactive oxygen species are necessary for the activation of p56(Hck), p72(Syk), and p77(Btk) by spores |
| GO:0035556 intracellular signal transduction | IDA PMID:11606584 Tyrosine residues in phospholipase Cgamma 2 essential for th... | ACCEPT | Summary: BTK directly transmits receptor signals through PLCgamma2 phosphorylation. Reason: The purified-protein and cellular complementation results establish BTK catalytic participation in intracellular signal transfer. This is stronger than a pathway-necessity inference alone; downstream lipid hydrolysis remains PLCgamma2 activity. Supporting Evidence: |
| GO:0035556 intracellular signal transduction | IDA PMID:15509800 Mechanism of B-cell receptor-induced phosphorylation and act... | ACCEPT | Summary: BTK transmits BCR signals to PLCgamma2 and calcium signaling. Reason: Ramos and murine B-cell experiments show Btk-dependent activating PLCgamma2 phosphorylation and lipase output. The cell and phosphosite distinctions in the abstract are retained rather than treating all PLCgamma2 phosphorylation as equivalent. Supporting Evidence: |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: The PH-domain-associated signaling inference agrees with BTK function. Reason: The InterPro mapping is independently supported by the kinase, PIP3-recognition and receptor-signaling experiments. A PH domain alone would not establish all pathway roles, but BTK has direct catalytic and cellular corroboration. |
| GO:0035556 intracellular signal transduction | IGI PMID:14656219 Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylat... | ACCEPT | Summary: BTK contributes to platelet intracellular signal transfer. Reason: The source examines receptor-dependent Syk and PLCgamma2 phosphorylation and reports Btk phosphorylation of PLCgamma2 peptides. This supports BTK signaling participation with the original P16885 genetic-interaction partner retained, without converting the assay into proof of every physical binding mode. Supporting Evidence: |
| GO:0035556 intracellular signal transduction | TAS PMID:11913944 B cell signaling. Introduction. | ACCEPT | Summary: BTK is a receptor-proximal intracellular signaling kinase. Reason: The short B-cell-signaling review places BTK with other proximal kinases; direct PLCgamma2 and BCR experiments independently substantiate this broad process. |
| GO:0038095 Fc-epsilon receptor signaling pathway | TAS Reactome:R-HSA-2454202 | KEEP AS NON CORE | Summary: BTK participates in Fc-epsilon-receptor signaling in mast cells. Reason: The cached Reactome pathway and the primary mouse mast-cell activation abstract support this receptor context. Retain it as a contextual deployment of BTK kinase function, without inferring every human histamine or systemic allergic outcome from the mouse activation assay. |
| GO:0042113 B cell activation | IEA GO_REF:0000117 | ACCEPT | Summary: BTK contributes to B-cell activation downstream of the BCR. Reason: The ARBA process inference is independently supported by Btk-dependent PLCgamma2 phosphorylation, calcium signaling and human B-cell biology. Its acceptance does not require assuming every ARBA predicate has been reconstructed. |
| GO:0042113 B cell activation | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BTK signaling enables B-cell activation. Reason: The review abstract explicitly describes BCR-linked calcium and NF-kappaB responses, with primary biochemical/cellular support. The core is receptor-proximal kinase action, rather than the aggregate disease phenotype. |
| GO:0042802 identical protein binding | IPI PMID:11577348 Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk... | UNDECIDED | Summary: The original BTK self-association experiment remains unresolved. Reason: The PMID:11577348 abstract establishes IBTK interaction with the BTK PH domain and inhibition of BTK, but it does not describe the BTKβBTK experiment underlying this identical-protein-binding assertion. The accessible publisher figure headings and supplementary descriptions did not establish that assay. Preserve the curated self-binding assertion and uncertainty; the paper's IBTK focus is not evidence against BTK self-association. Supporting Evidence: |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BTK promotes BCR-dependent canonical NF-kappaB signaling. Reason: The complete review abstract explicitly states that the BCR-dependent NF-kappaB pathway requires functional Btk. This supports pathway regulation downstream of BTK kinase signaling; it does not assign BTK direct DNA-binding or NF-kappaB transcription-factor activity. Supporting Evidence: |
| GO:0043274 phospholipase binding | IPI PMID:11606584 Tyrosine residues in phospholipase Cgamma 2 essential for th... | ACCEPT | Summary: BTK recognizes and interacts with its phospholipase substrate PLCgamma2. Reason: Accept the curated PLCG2 interaction in light of direct purified-substrate phosphorylation in PMID:11606584. Phospholipase binding does not require a stable isolated complex; transient noncovalent substrate recognition is consistent with the established kinase mechanism. The retrieved primary biochemical sections establish the enzymeβsubstrate relationship; the separate gel-filtration complex assay concerns PLCgamma2βBLNK, and is not misreported as a BTK binding assay. Supporting Evidence: |
| GO:0043274 phospholipase binding | IPI PMID:14656219 Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylat... | ACCEPT | Summary: BTK recognizes and interacts with its phospholipase substrate PLCgamma2. Reason: Accept the curated PLCG2 interaction in light of direct purified-substrate phosphorylation in PMID:11606584. Phospholipase binding does not require a stable isolated complex; transient noncovalent substrate recognition is consistent with the established kinase mechanism. The original PMID:14656219 full target-level IPI experiment remains uninspected; its abstract reports platelet signaling and peptide phosphorylation. Independent target evidence and curator deference support the broad binding assertion without claiming that particular experiment was verified. |
| GO:0045087 innate immune response | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BTK also supplies kinase activity to innate immune signaling. Reason: The original review abstract does not detail its innate-immunity discussion. Independent primary DDX41/STING and NLRP3 studies directly establish BTK substrate phosphorylation and pathway effects, supporting this broad process with explicit source-specific limits. |
| GO:0045121 membrane raft | IDA PMID:15046600 Btk-dependent regulation of phosphoinositide synthesis. | ACCEPT | Summary: BTK associates with membrane-raft signaling assemblies. Reason: The source abstract describes BTK-associated phosphoinositide-kinase recruitment to lipid rafts. Independent human Daudi/Raji raft-complex experiments in PMID:19214191 corroborate the compartment. This is membrane association, not evidence that all BTK molecules are constitutively raft-bound. |
| GO:0045121 membrane raft | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic raft localization agrees with human signaling-complex evidence. Reason: The combined ARBA/mouse/subcellular mapping is corroborated by the phosphoinositide-recruitment abstract and inspected human B-cell raft-association experiments. The entire ARBA inference chain was not reconstructed. |
| GO:0045121 membrane raft | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse-to-human raft localization is independently corroborated. Reason: The original mouse donor experiment was not separately inspected, but the human Daudi/Raji raft-complex evidence in PMID:19214191 supports the compartment directly. Retain the ISS source and do not treat orthology as the sole available support. |
| GO:0045579 positive regulation of B cell differentiation | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | KEEP AS NON CORE | Summary: BTK signaling promotes B-cell differentiation. Reason: The review abstract explicitly connects BTK with B-lymphocyte development and differentiation and human XLA. Retain the developmental outcome as a non-core consequence of receptor signaling; the kinase/PIP3-recognition activities define the mechanistic core. Supporting Evidence: |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat donor trace identifies PMID:12220673, which includes BTK imaging after siRNA depletion. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor trace identifies PMID:12220673, which includes BTK imaging after siRNA depletion. The accessible abstract does not resolve the exact perinuclear signal, construct or cell line; cytoplasmic and nuclear pools alone do not establish perinuclear enrichment. Retain this finer localization as unresolved pending the original imaging. Supporting Evidence: |
| GO:0050766 positive regulation of phagocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Full rat donor PMID:28352114 reports that selective BTK inhibition reduces excessive peritoneal-macrophage phagocytosis in arthritis. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. Full rat donor PMID:28352114 reports that selective BTK inhibition reduces excessive peritoneal-macrophage phagocytosis in arthritis. Native mouse PMID:23544144 independently distinguishes reduced E. coli-fragment uptake from preserved Listeria uptake after Btk loss. Retain context-dependent positive phagocytosis regulation, not a universal uptake requirement. Supporting Evidence: PMID:28352114 reduce the excessive PMΦ phagocytosis to normal level in AA rats |
| GO:0050852 T cell receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: BTK has an experimentally supported contextual role in T-cell receptor signaling. Reason: The TCR IBD at PTN000700360 has the exact two MGI seeds shown in GOA; neither their number nor the prominence of ITK/Txk in T cells refutes the node placement. Independent mouse Btk-null experiments report reduced TCR-induced PLCgamma1 phosphorylation, endogenous BTKβPLCgamma1 association and kinase-dependent effects in transfected cells. This supports retaining the inherited process as non-core. It is not a direct human T-cell assay or purified catalytic reconstitution, and the complete PAINT tree was not inspected. |
| GO:0050853 B cell receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: BTK directly participates in B-cell receptor signaling. Reason: The BCR IBD at PTN000700360 is supported by the exact TEC and BTK identifiers in GOA. BTK appearing as its own descendant evidence is expected and is not a propagation defect. The cached biochemical study reports Btk phosphorylation of PLCgamma2 in the BLNK-organized BCR pathway and functional complementation in chicken DT40 cells. This independently supports the pathway role while retaining the original inherited source assertion and its comparative assay boundaries. |
| GO:0050853 B cell receptor signaling pathway | IDA PMID:15509800 Mechanism of B-cell receptor-induced phosphorylation and act... | ACCEPT | Summary: BTK participates directly in B-cell receptor signaling. Reason: The source reports Btk-dependent PLCgamma2 activation following BCR stimulation in human Ramos and murine splenic B cells. The functional signaling role is directly supported, with the distinct Tyr1217 behavior retained as an assay boundary. Supporting Evidence: |
| GO:0050853 B cell receptor signaling pathway | TAS PMID:19290921 Bruton's tyrosine kinase (Btk): function, regulation, and tr... | ACCEPT | Summary: BCR signaling is a principal BTK pathway. Reason: The complete review abstract describes the BCRβBTKβcalcium/NF-kappaB relationship, corroborated by primary PLCgamma2 activation experiments. This is a central kinase-dependent signaling role. |
| GO:0050864 regulation of B cell activation | IEA GO_REF:0000117 | ACCEPT | Summary: BTK regulates B-cell activation through receptor-proximal phosphorylation. Reason: The ARBA regulatory-process inference agrees with direct PLCgamma2 activation and downstream calcium/NF-kappaB signaling. It does not imply that every context has the same quantitative response. |
| GO:0050869 negative regulation of B cell activation | IEA GO_REF:0000107 | MODIFY | Summary: The rat donor PMID:25545336 explicitly shows that BTK inhibitors attenuate anti-IgD/TLR9-induced B-cell activation. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The rat donor PMID:25545336 explicitly shows that BTK inhibitors attenuate anti-IgD/TLR9-induced B-cell activation. Inhibition of a positive signaling kinase is not evidence that the kinase negatively regulates activation. Correct the sign to positive regulation of B-cell activation, corroborated by native BCR/PLCgamma2 biology. This source-specific correction does not deny the distinct xid pre-B-cell IL-7 negative-proliferation context. Proposed replacements: positive regulation of B cell activation Supporting Evidence: PMID:25545336 Highly selective inhibitors of BTK, SYK, and PI3KΞ΄ dose-dependently attenuated B cell activity |
| GO:0061516 monocyte proliferation | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact rat donor trace resolves these blood-cell abundance/proliferation claims to PMID:32484067, a zanubrutinib nonclinical toxicology study. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The exact rat donor trace resolves these blood-cell abundance/proliferation claims to PMID:32484067, a zanubrutinib nonclinical toxicology study. The accessible abstract does not expose the lineage-specific counts, proliferation readout or mechanistic attribution, and a drug-associated count change alone would not distinguish production, survival and redistribution. Preserve the transferred claim pending the relevant tables, rather than infer a direct mouse lineage-production function or declare the rat result false. Supporting Evidence: |
| GO:0070664 negative regulation of leukocyte proliferation | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact rat donor trace resolves these blood-cell abundance/proliferation claims to PMID:32484067, a zanubrutinib nonclinical toxicology study. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The exact rat donor trace resolves these blood-cell abundance/proliferation claims to PMID:32484067, a zanubrutinib nonclinical toxicology study. The accessible abstract does not expose the lineage-specific counts, proliferation readout or mechanistic attribution, and a drug-associated count change alone would not distinguish production, survival and redistribution. Preserve the transferred claim pending the relevant tables, rather than infer a direct mouse lineage-production function or declare the rat result false. Supporting Evidence: |
| GO:0071226 cellular response to molecule of fungal origin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat donor PMID:10744701 directly measures BTK activation after fungal-spore exposure in alveolar macrophages, with species-dependent activation kinetics and endogenous ROS dependence. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. Rat donor PMID:10744701 directly measures BTK activation after fungal-spore exposure in alveolar macrophages, with species-dependent activation kinetics and endogenous ROS dependence. Retain the conserved stimulus-response attribution as contextual rather than relabeling it as a native mouse assay or inferring the complete antifungal effector program. Supporting Evidence: PMID:10744701 p56(Hck), p72(Syk), and p77(Btk) were activated faster and to a greater extent by spores from A. candidus |
| GO:0097190 apoptotic signaling pathway | TAS PMID:8688094 BTK as a mediator of radiation-induced apoptosis in DT-40 ly... | KEEP AS NON CORE | Summary: BTK can mediate radiation-induced apoptotic signaling. Reason: The abstract describes Btk-null chicken DT40 lymphoma cells resistant to radiation-triggered apoptosis and rescue with wild-type human BTK, with the kinase domain required. Retain this contextual apoptotic pathway; it does not mean BTK universally promotes apoptosis or mediates the same stress response in all normal human tissues. Supporting Evidence: |
| GO:0141111 positive regulation of cGAS/STING signaling pathway | IDA PMID:25704810 Bruton's tyrosine kinase phosphorylates DDX41 and activates ... | UNDECIDED | Summary: The available DDX41βSTING evidence does not resolve the more specific cGAS-initiated term. Reason: PMID:25704810 directly reports BTKβDDX41/STING association, DDX41 Tyr414 phosphorylation and STING-dependent interferon signaling. Official GO:0140896 defines the regulated pathway as initiated through cGAS and cGAMP, while the accessible source abstract centers DDX41 and does not establish cGAS dependence. Full relevant Results were unavailable. Preserve the experimental annotation as unresolved rather than infer that the paper cannot contain the needed experiment. Supporting Evidence: |
| GO:0150153 positive regulation of interleukin-17A production | IEA GO_REF:0000107 | UNDECIDED | Summary: Full rat donor PMID:28352114 reports that systemic TNF-alpha and IL-17A were only slightly affected by the inhibitor and directs the result to supplementary data. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. Full rat donor PMID:28352114 reports that systemic TNF-alpha and IL-17A were only slightly affected by the inhibitor and directs the result to supplementary data. The direction, magnitude and mechanistic attribution needed for a specific positive IL-17A-regulation transfer are not settled by the inspected main text. Do not substitute the much clearer IL-6 or IL-10 findings for this cytokine. Supporting Evidence: PMID:28352114 TNF-Ξ± and IL-17A was slightly affected |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | IDA PMID:34554188 BTK operates a phospho-tyrosine switch to regulate NLRP3 inf... | ACCEPT | Summary: BTK promotes NLRP3 inflammasome assembly through direct phosphorylation. Reason: The inspected Results combine direct BTK kinase assays with native-complex sizing, ASC recruitment/oligomerization and NLRP3 tyrosine mutants. Human PBMC/XLA and mouse macrophage experiments support a catalytic contribution to assembly. The paper also discusses different outcomes under strong TLR priming, so acceptance is bounded to demonstrated activation settings rather than universal positive regulation. Supporting Evidence: |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic NLRP3-assembly regulation agrees with direct target evidence. Reason: Independent PMID:34554188 provides BTK/NLRP3 kinase and assembly experiments, including mutant reconstitution and human PBMC observations. This supports the molecular mechanism despite an uninspected ARBA predicate/mouse donor chain. Context-dependent signaling sign is retained. |
| GO:1901647 positive regulation of synoviocyte proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain contextual regulation of synovial-cell proliferation with the systemic assay boundary explicit. Reason: Full rat donor PMID:28352114 measures reduced synovial-cell proliferation after systemic selective BTK-inhibitor treatment of arthritic rats. Retain this regulatory attribution as a non-core disease-context outcome, without claiming a synoviocyte-intrinsic kinase mechanism or a direct target-species assay. Regulation of proliferation does not require BTK to be a cell-cycle enzyme or to act within the proliferating cell; indirect immune-mediated regulation remains compatible with the term. Supporting Evidence: PMID:28352114 the proliferations in the CHMFL-BTK-11 |
| GO:1990959 eosinophil homeostasis | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact rat donor trace resolves these blood-cell abundance/proliferation claims to PMID:32484067, a zanubrutinib nonclinical toxicology study. Reason: For the human annotation, distinguish conserved ortholog biology from a direct human assay. The exact rat donor trace resolves these blood-cell abundance/proliferation claims to PMID:32484067, a zanubrutinib nonclinical toxicology study. The accessible abstract does not expose the lineage-specific counts, proliferation readout or mechanistic attribution, and a drug-associated count change alone would not distinguish production, survival and redistribution. Preserve the transferred claim pending the relevant tables, rather than infer a direct mouse lineage-production function or declare the rat result false. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which original reagents and accession mappings resolve Q9Y2I7/PIKFYVE versus PIP5K in PMID:15046600 and P21145/MAL versus the Toll adaptor Mal/TIRAP in PMID:22366891?
Q: Which target-specific assays establish the unresolved BTK screen interactions, self-association and PLCgamma2 physical-binding assertions?
Q: Does the complete PMID:25704810 experiment demonstrate cGAS/cGAMP-dependent signaling in addition to DDX41βSTING signaling?
Q: What are the original rodent experiments and relevant cellular contexts for the unresolved cytokine, proliferation, hypersensitivity and subcellular-location transfers?
Q: How do BTK-A and BTK-C differ in endogenous localization, substrate selection and cell-type expression, beyond the domain constructs used here?
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