This review assesses all 149 unique GOA assertions (150 raw rows; the repeated WASP interaction differs in assignment/date), preserving every machine term, evidence code, qualifier and supporting accession. The reviewed human UniProt entry is Q06187 (659 amino acids); BTK-A Q06187-1 and BTK-C Q06187-2 remain the two recorded alternative products. No isoform-specific activity or distribution is assumed from constructs that test only a domain or one product. No NEW annotation is proposed.
The normal Falcon attempt used the installed deep-research client 0.2.7rc1 and the configured perplexity-lite fallback. Both failed DNS and produced no provider files. The record is provider-attempt-assessment.json in the session's TMP work; it is an explicitly filtered outcome that omits credential-bearing traceback material. The ordinary reference command found all 29 original PMID caches already present. Manual source assessment follows below; no prose was manufactured as a provider result.
The canonical BTK source files and all 70 original publication/Reactome caches were hashed before work and remained unchanged. PMID:8892607 was an existing remote cache restored locally from its exact main blob by the importer; it was not replaced with the newly fetched variant. The source importer also retained all other differing fetched variants separately. This review retains all 79 original reference identifiers and titles and adds the normally fetched PMID:31431692 because it materially resolves the T-cell IBA interpretation.
BTK's principal activity is nonreceptor protein tyrosine phosphorylation. PMID:11606584(https://pubmed.ncbi.nlm.nih.gov/11606584/) reports purified Btk phosphorylation of recombinant PLCgamma2 and a functional requirement for defined PLCgamma2 tyrosines. The human PLCgamma2 rescue was performed in chicken DT40 cells; the abstract does not identify the purified Btk construct species. PMID:15509800(https://pubmed.ncbi.nlm.nih.gov/15509800/) separately reports Btk-dependent PLCgamma2 activating phosphosites in human Ramos and murine splenic B cells. Calcium/NF-kappaB outputs belong to this pathway mechanism. PLCgamma2 performs the lipid hydrolysis, and ATP binding is part of BTK catalysis rather than a separate core activity. The source phospholipase-activator assertion is retained as a non-core mechanistic description; full original binding-assay access was unavailable.
Own PIP3 recognition is a distinct molecular activity that positions the kinase. PMID:17823121(https://pubmed.ncbi.nlm.nih.gov/17823121/) reports quantitative PH-domain lipid-binding experiments and PIP3-dependent recruitment in NIH 3T3 cells; PMID:10196179(https://pubmed.ncbi.nlm.nih.gov/10196179/) and PMID:10602036(https://pubmed.ncbi.nlm.nih.gov/10602036/) distinguish isolated PH-domain reporters from full-length Btk-GFP. The two core units therefore describe kinase action and PIP3 recognition, without assigning phosphoinositide synthesis or hydrolysis to BTK. Cytosol and stimulus-dependent peripheral plasma-membrane recruitment are compatible locations. Nuclear shuttling in PMID:11016936(https://pubmed.ncbi.nlm.nih.gov/11016936/) includes wild-type/endogenous evidence and is retained as a contextual localization, not dismissed because deletion mutants accumulate more strongly.
For innate signaling, the normally cached Reactome TIRAP event and PMID:25704810(https://pubmed.ncbi.nlm.nih.gov/25704810/) support kinase participation. The latter abstract directly names DDX41/STING interactions, DDX41 phosphorylation and interferon effects. The narrower cGAS/STING source term remains UNDECIDED: official GO:0140896 explicitly starts with cGAS/cGAMP, while the inspected abstract centers DDX41 and the relevant full experiment was unavailable. An abstract omission is not a claim that no such experiment exists.
PMID:34554188(https://pubmed.ncbi.nlm.nih.gov/34554188/) was read at the relevant unique Results, Methods and Discussion passages: purified BTK/NLRP3, kinase-dead K430E and inhibitor controls, target-tyrosine mutants, native-complex/ASC assays, human PBMC/XLA and mouse macrophage reconstitution. Those assays identify BTK as a catalytic participant in assembly, not merely a necessary substrate. The study itself discusses different effects under stronger TLR priming. Its positive NLRP3-assembly annotation is accepted in the demonstrated settings, without claiming permanent mature-complex membership or universal positive inflammatory regulation. Figure images and complete supplements were not inspected.
The explicit ClinGen task instruction is to retain supported generic binding rather than remove it solely for low information content; see the current campaign policy. This is a task-specific curation instruction, not fabricated external maintainer approval. Where a justified specific molecular function exists, the review refines it: PKC-theta binding and TFII-I/Bright binding become protein kinase C binding or DNA-binding transcription factor binding. These are binding roles of BTK, not transfer of the partner's catalytic or transcription-factor activity.
Bicra independently supplied the 17-row binding consultation. Four interactions remain supported non-core, including WASP, Sab, the bounded ADAM15 SH3-domain assay, and BLNK with explicit separate thesis corroboration. BTK supplies the SH3 domain in the WASP/Sab assays; reversing these into BTK SH3-domain-binding activity would misdescribe the direction. Nine source-specific assertions remain uncertain because their target tables or assays were unavailable. A paper foregrounding BRK/PTK6, IBTK or a large screen is not sufficient reason to reject a BTK assertion.
Two partner identities require particular care. Source Q9Y2I7 is PIKFYVE, whereas the PMID:15046600 abstract discusses PIP5Ks that produce PI(4,5)P2; this is unresolved rather than silently remapped. Source P21145 is MAL, while PMID:22366891 discusses the Toll adaptor called Mal/TIRAP; original reagent/accession reconciliation is needed. The human neutrophil ROS/apoptosis phenotype from that paper can be read independently of the unresolved partner ID. ROS production regulation is also different from response to ROS, so it does not automatically validate the corresponding rat transfer.
The 41 cached Reactome summaries were read individually. Many rows annotate only cytosol; their titles describe IRAK, VAV, PLC or receptor events, which do not make BTK the enzyme executing every reaction. Accurate cytosolic participation is retained without promoting every intermediate complex to a stable core complex. The TLR recruitment event explicitly summarizes differing human cytokine observations, supporting caution about a universal sign for IL-6/TNF regulation.
The five IBA rows were joined exactly to the cached PTHR24418 PAINT IBD records. PTN000700360 carries adaptive immunity and BCR/TCR pathway assertions, PTN001231474 the non-membrane-spanning kinase assertion, and PTN002521457 the plasma-membrane assertion. Target self-inclusion is legitimate descendant experimental grounding. Donor count is not used as a strength score. Complete ancestral trees/MSAs and all donor experimental records were not reconstructed, so the review does not invent a pre-duplication history.
The bounded IBA consultant found PMID:31431692(https://pubmed.ncbi.nlm.nih.gov/31431692/), then ROOT used the unchanged normal fetcher to obtain its cache. The authenticated source was independently read for doubly sorted mouse T cells, Btk-null antibody controls, TCR activation, endogenous BTK–PLCgamma1 association, and HEK293T wild-type/K430R comparisons. This supports retaining the TCR IBA as contextual non-core activity. It is not a direct primary human T-cell catalytic assay, and the transfected-cell mutant comparison is not purified reconstitution. No new source quotations are added for this paper.
The rat A0A0G2K6M9 and mouse P35991 identities were checked against official NCBI/MGI records. This identity check does not reconstruct their individual donor assays. Fine transferred cytokine, hypersensitivity, proliferation, organelle and cell-homeostasis contexts therefore remain UNDECIDED when no independent exact evidence was accessible. Broad human B-cell signaling and neutrophil-survival evidence can support selected contextual outcomes without asserting that the original rodent experiment was inspected. The mesoderm-development row likewise remains unresolved because the cited clinical abstract does not expose its supporting experiment.
The complete substantive abstracts were read for all original PMID caches; PMID:16969585 contains bibliographic text rather than a substantive abstract. For that journal assertion, the primary author's thesis abstract supplies bounded independent corroboration, not a claim that the original journal assay was read. PMID:22939624, 25910212 and 33961781 have partial extractions despite full-text flags; the required BTK target tables were not available. Selected target Results/Methods for 19214191, 25825872 and 9012831 were read by the binding consultant, and selected complete paragraphs for 34554188 and 31431692 by the owner. The YAML reference reviews distinguish cache availability from actual reading. No uninspected figure image is claimed.
Source-reading transcript pointers include e0bfa8 (primary abstracts), af9088/7d78c7/1c91c0 (NLRP3 assay/context passages), 69b0fe (all cached Reactome event summaries), c48e5e (new T-cell primary Results/Methods), and the consultants' own saved reading notes. These are session-local workflow pointers; durable scientific evidence is provided by the PMID/DOI and ontology links above. The saved web responses document successful official term/identity reads and failed full-text/QuickGO attempts honestly. No access success is inferred from a failed endpoint.
The two-core/description consultation by Bicra found no synthesis defect beyond a source-record sentence, which was moved out of the biological description into these notes. The five-IBA consultation by the child and the 17-binding consultation by Bicra are disclosed partial consultations, not whole-gene approval. ROOT remains the independent whole-science reviewer before canonical application.
The draft keeps DRAFT status because unresolved evidence and normal validation advisories remain. Campaign progress and biological review status are separate; no annotation uncertainty is converted to a confirmed function by publication.
Normal schema, best-practice, GO term/label, GOA and reference validation passed (actual 6c99cd). Four advisories concern the supported non-core generic-binding rows 28, 33, 38 and 40. They are retained under the explicit task policy, with source-specific access and interaction-direction limits. The single ten-word PIP3 quote is an exact canonical-cache substring and stays within the 25-word per-source budget. All 149 source objects, both alternative products and the 79 original reference ID/title pairs are exact; the only added reference is the normally fetched T-cell study. Canonical application remains pending ROOT whole-science peer.
The exact independently reviewed candidate and manual notes were applied after ROOT’s whole-science PASS. Normal canonical validation passed with four documented generic-binding warnings; a standard codex/gpt-6 CREATE history and targeted HTML rendering passed. All 149 machine-sourced assertions, two alternative products, 79 original reference identities and immutable normal source files are preserved. PMID:31431692 is the sole added reference (80 total); there are no NEW assertions. DRAFT and the 33 UNDECIDED source assessments remain. Remote publication is a separate ROOT-owned step.
The phospholipase-activator assertion is refined to GO:0004715 non-membrane spanning protein tyrosine kinase activity. Official AmiGO shows GO:0016004 under lipase activator, enzyme activator and molecular function regulator activity. The regulator definition excludes covalent target modification, so phosphorylation-mediated activation does not establish that MF. This definition applies independently of the standing project exception for generic protein binding (GO:0016004, GO:0098772).
Both GO:0043274 assertions retain their original PLCG2 accession and are now ACCEPT. The earlier requirement to identify a stable isolated complex was stronger than the GO binding definition. The established direct enzyme–substrate relationship, together with expert-curated IPI evidence, supports phospholipase binding; it does not require a separate independent allosteric function. This is curator deference with explicit access limits, not a claim to have independently verified both original physical-interaction experiments.
Additional primary access: the institutional author PDF of PMID:11606584 identifies human BTK constructs and documents purified-protein phosphorylation. Its separate complex-separation experiment concerns PLCgamma2–BLNK. Selected Methods, Results, captions and Discussion text were inspected, not all images or supplementary material. The canonical normal cache remains unchanged and abstract-only; the reference finding's availability flag now reflects actual external full-text access. PMID:14656219 remains abstract-only in the inspected evidence; the direct PMC page presented a browser challenge. Neither full-paper absence nor a high-affinity BTK–PLCG2 complex is inferred.
The two kinase-row explanations now reflect the resolved human construct provenance. A short exact cached kinase anchor is reused once in the relevant row and once in the kinase core, totaling 22 words from PMID:11606584 across both uses. The prior PIP3-binding anchor is preserved. No source cache or existing history changed.
The advisory SH3 suggestions were considered without reversing binding direction. The inspected ADAM15 source identifies BTK SH3 binding and describes the peptide-array method, but its exact target-level motif map was not newly examined here. The WASP abstract establishes SH3-domain association but does not independently map the precise BTK-recognized motif in the inspected text. Both existing bounded non-core decisions remain. The Sab source explicitly lacks a proline-rich sequence, so no proline-region function is transferred to that interaction.
The proteoglycan-catabolism orthology row remains UNDECIDED. Its reason identifies why signaling necessity alone would be insufficient; it does not establish that the uninspected donor experiment lacks a participating BTK mechanism. No new assertion or categorical source error is inferred from that limitation.
All 149 machine-sourced objects, two alternative products, reference identities, descriptions of the two core mechanisms and prior notes are preserved. Actions are now 96 ACCEPT, 16 KEEP_AS_NON_CORE, 31 UNDECIDED and six MODIFY. No NEW or REMOVE rows are added. This focused candidate awaits independent peer review and canonical application; validation results are recorded below after the normal checks.
Normal full candidate validation, including ontology terms, references and GOA consistency, passed with zero errors and the same four documented generic-binding warnings. DRAFT is unchanged and no decisions are PENDING.
The independently reviewed follow-up was applied after checking the original file bytes. The 149 machine-source assertions and two products are preserved. The phospholipase-regulator assertion is refined to the established kinase activity, and the two PLCG2-binding assertions are accepted with direct substrate-recognition evidence and explicit source-access limits. The resulting decisions are 96 ACCEPT, 16 KEEP_AS_NON_CORE, 31 UNDECIDED and six MODIFY. The original notes, source caches and prior history records are preserved.
All 149 baseline rows were reviewed across B-cell and non-B-cell functions. Original row payloads and raw UniProt/GOA files are preserved; no new annotation was proposed. The shared acquisition ran actual Falcon/fallback attempts and normal publication retrieval; failed providers were not replaced with fabricated reports.
The molecular core is non-receptor tyrosine phosphorylation; PH-domain PIP3 recognition supplies recruitment rather than lipid synthesis. PLCgamma activation by covalent phosphorylation does not establish the independent noncovalent phospholipase-activator MF. Native BCR, mast-cell and myeloid contexts remain distinct; full PMID:34554188 supports NLRP3 substrate phosphorylation and assembly under tested priming/activation conditions, not universal positive inflammatory action. PMID:23544144 establishes negative cytokine regulation during mouse Listeria infection. PMID:31431692 supports a contextual native mouse T-cell role and prevents dismissal of the TCR IBA merely because ITK/TXK are more familiar T-cell kinases.
The rat donor A0A0G2K6M9 / RGD:1359683 was traced through the current QuickGO annotation API to original experimental papers. The durable mouse Btk source-analysis JSON is a provenance trace only, never functional supporting evidence. Normally fetched PMID:25545336 explicitly shows that selective BTK inhibitors attenuate B-cell activation; negative regulation by the drug was incorrectly transferred as negative regulation by BTK. The existing source row is therefore corrected by MODIFY to positive regulation, with original machine fields unchanged. This does not contradict the separate xid pre-B-cell IL-7 negative-proliferation context in PMID:7680896.
Full PMID:28352114 resolves several rat arthritis inferences: systemic treatment lowers IL-6 and raises IL-10, while TNF/IL-17A change only slightly; peritoneal macrophage uptake and disease-state splenic proliferation differ from the isolated normal LPS-stimulated B-cell assay, where inhibitors did not significantly reduce proliferation. Synovial-cell proliferation after systemic treatment does not resolve a synoviocyte-intrinsic BTK mechanism; its existing regulatory attribution is retained as a non-core disease-context outcome, since regulation does not require cell autonomy. The specific IL-17A direction remains unresolved. The toxicity-source PMID:32484067 and remibrutinib-source PMID:32083858 remain abstract-limited, so blood-lineage counts and proteoglycan-catabolism assignments are not adjudicated from general drug efficacy/safety. PMID:10744701 directly documents fungal-spore/endogenous-ROS activation of rat BTK; it does not imply BTK responds to exogenous H2O2 alone.
The old ClinGen-specific retention instruction in the historical notes is superseded by the current module-audit protein-binding policy. Four experimentally supported but uninformative bare-binding claims (BLNK, ADAM15, WASP, Sab) are removed without denying their interactions or reversing domain-binding direction. Existing source-specific uncertainties and informative partner-class refinements remain. No experimental annotation is rejected because its abstract foregrounds another protein.
The earlier draft wording that called the systemic arthritis synoviocyte-proliferation attribution over-annotated is superseded. Regulation of proliferation does not require BTK to act within the proliferating synoviocyte. Full PMID:28352114 supports a disease-context, cell-extrinsic regulatory effect; the existing claim is retained as KEEP_AS_NON_CORE with this limit, without asserting synoviocyte-autonomous BTK.