BRSK2

Summary: Conserved cell-cycle involvement is retained as a contextual BRSK-family function.

Reason: The PAINT assertion is retained without a claim that its complete ancestral placement was re-evaluated. Human BRSK2 has target-level cell-cycle evidence in PMID:23029325; its presence among the descendants is legitimate experimental grounding, not circularity. The measured G2/M accumulation supports this context but does not identify the direction or molecular step of transition control.

Summary: The electronic G2/M assignment is consistent with the measured human cell-cycle phenotype.

Reason: The ARBA rule is retained in the context of PMID:23029325, where BRSK2 overexpression increases the G2/M population. This does not demonstrate faster G2-to-M passage, an endogenous checkpoint mechanism, or catalytic participation in APC/C-mediated degradation. The full ARBA rule conditions were not independently reconstructed.

Summary: BRSK2 abundance affects the G2/M cell population in cultured human cells.

Reason: The inspected Results report increased G2/M fractions after wild-type or KEN-box-mutant BRSK2 expression in HeLa and H1299 cells. Retain the curated transition context, bounded by the fact that a static phase distribution does not resolve entry, exit, or arrest kinetics. The paper establishes BRSK2 as an APC/C-Cdh1 substrate, not the degradation catalyst; its Cdc25C phosphorylation statement refers to unpublished work and is not treated as an assay performed here.

Summary: Magnesium supports BRSK2 phosphotransfer chemistry.

Reason: The original IDA annotation is consistent with the Mg-dependent protein-kinase cofactor recorded for BRSK2 in UniProt and the activation/kinase experiments in PMID:14976552. The available abstract does not expose an isolated metal-binding assay; retain the curator-supported catalytic cofactor property without making it a distinct core function.

Summary: BRSK2 is an active protein kinase.

Reason: The InterPro kinase-domain assignment agrees with direct BRSK2 activation and substrate-phosphorylation evidence (PMID:14976552, PMID:21985311). This broad electronic annotation is correct; the more precise serine/threonine and tau kinase annotations are reviewed separately.

Summary: BRSK2 has protein serine/threonine kinase activity.

Reason: PMID:14976552 explicitly includes human BRSK2 among AMPK-related kinases activated by the LKB1 complex, and PMID:21985311 directly includes BRSK2 in tau serine phosphorylation assays. These observations support the established catalytic identity rather than treating BRSK2 only as an LKB1 substrate.

Summary: The EC/ARBA serine/threonine kinase mapping matches BRSK2 catalysis.

Reason: The combined electronic mapping to EC:2.7.11.1 is supported by the active kinase domain and experimental phosphotransfer evidence in PMID:14976552 and PMID:21985311. No target-specific loss of this catalytic function is apparent.

Summary: The rat BRSK2 ortholog supports conserved protein serine/threonine kinase activity.

Reason: The source accession D3ZML2 is rat BRSK2, verified by the official NCBI protein record. The transfer is independently corroborated by human BRSK2 kinase evidence in PMID:14976552 and PMID:21985311; it does not depend solely on a generic family assignment.

Summary: BRSK2 binds COPS5/Jab1 in a context that regulates BRSK2 turnover.

Reason: PMID:22609399 reports GST pull-down and immunoprecipitation supporting BRSK2-Jab1 interaction, corresponding to the source partner Q92905/COPS5. Jab1 promotes ubiquitination and degradation of BRSK2; this does not establish BRSK2 as a ubiquitin ligase or degradation catalyst. Retain the supported interaction under the explicit ClinGen task instruction; a specific replacement molecular activity is not established.

Summary: The BRSK2-YWHAE interaction needs target-specific evidence from the 14-3-3 study.

Reason: The source partner P62258 is YWHAE/14-3-3 epsilon, also listed as a BRSK2 interactor in UniProt. PMID:36931259 is a human 14-3-3 client study, but the available abstract does not identify the BRSK2 pair or its assay. The supporting matrix/full relevant result was not inspected. This access gap does not establish a false interaction or justify removal.

Summary: ATP binding is part of BRSK2's kinase mechanism.

Reason: The original IDA annotation is consistent with the experimentally active BRSK2 kinase in PMID:14976552 and tau phosphorylation in PMID:21985311. ATP binding is a required catalytic feature, not a separate core molecular activity; the isolated binding measurement is not visible in the abstract-only cache.

Summary: The kinase-domain ATP-binding assignment is sound.

Reason: The InterPro protein-kinase and ATP-binding-site signatures agree with BRSK2's active kinase domain and experimental substrate phosphorylation. Retain this mechanistic property without duplicating the kinase core.

Summary: Cytoplasmic localization is consistent with independently observed human BRSK2 distribution.

Reason: The cited source's complete abstract reports endogenous BRSK2 redistribution to the ER under stress; its individual microscopy panels and listed corrigendum were not recovered. Broad cytoplasmic localization is independently consistent with the curated UniProt record and the inspected mitotic centrosome localization in PMID:23029325. Retention does not imply that the original unstressed cytoplasmic image was inspected.

Summary: The cytoplasmic location is retained with an explicit limit on the original imaging evidence.

Reason: The original abstract reports BRSK2-VCP colocalization, but the microscopy panels were inaccessible. Broad cytoplasmic localization is corroborated by the reviewed UniProt record and PMID:23029325; the location is not inferred solely from VCP binding.

Summary: ER association is supported as a stress-dependent location.

Reason: The original source's exact imaging panel was not accessible. Independent PMID:22713462 explicitly reports endogenous BRSK2 recruitment to the ER during stress, supporting this location while leaving its original panel-level evidence and basal distribution unresolved. ORGANELLES check (2026-11-04, ER batch 1). BRSK2 is a soluble cytosolic kinase with no signal peptide, TM segment or retention motif in its UniProt record; its ER pool is a stress-induced recruitment of endogenous protein (tunicamycin) and an association with VCP/p97 at ERAD sites, i.e. a pool on the cytosolic face. Like a recruited pool on the mitochondrial surface, this supports the organelle but neither the ER membrane nor the lumen, so no sub-compartment row is added. The curator read the full text of PMID:23907667, whose abstract reports BRSK2-VCP co-localization but does not itself name the ER, so the IDA is deferred to and kept non-core.

Summary: The ER-location mapping agrees with experimentally reported stress-dependent recruitment.

Reason: The UniProt subcellular-location mapping is consistent with PMID:22713462. Retain the ER location as conditional recruitment; it does not imply ER-lumen residence or constitutive localization in every cell type. ORGANELLES check (2026-11-04, ER batch 1). The row maps UniProt SL-0095; the UniProt "Endoplasmic reticulum" item has no evidence tag, but the record's note states the tunicamycin-induced recruitment and its subcellular-location reference is PMID:22713462, whose abstract reports endogenous BRSK2 moving to the ER under ER stress. The organelle claim holds as a conditional, cytosolic-face pool; no sub-compartment is supportable for a soluble kinase without membrane features, so the row stays at the root, KEEP_AS_NON_CORE, consistent with the IDA ER row.

Summary: The conserved centrosomal location has direct experimental grounding on human BRSK2.

Reason: PMID:23029325 reports BRSK2 colocalization with gamma-tubulin from prophase through cytokinesis in HeLa cells, but not detectable centrosomal colocalization in interphase. This supports retaining the inherited location in a mitotic context. The complete PAINT tree was not read; target BRSK2 in the descendant list is not circular evidence.

Summary: BRSK2 localizes to centrosomes during mitosis in HeLa cells.

Reason: The inspected immunofluorescence Results and Methods use BRSK2 and gamma-tubulin staining and distinguish mitotic from interphase distribution. Retain this cell-cycle-dependent location; colocalization does not establish phosphorylation of gamma-tubulin or another centrosomal protein.

Summary: The centrosome-location mapping is supported in a mitotic context.

Reason: The UniProt subcellular-location mapping agrees with the direct localization experiment in PMID:23029325. Retain the location without extending the observed mitotic pattern to all interphase cells or tissues.

Summary: BRSK2 directly catalyzes protein phosphorylation.

Reason: PMID:14976552 establishes activation of BRSK2 kinase activity by LKB1; independent PMID:21985311 directly tests BRSK2 phosphorylation of tau. Thus BRSK2 executes the phosphotransfer step rather than merely being phosphorylated by another kinase.

Summary: Conserved SAD-kinase signaling contributes to axon formation.

Reason: The cached PAINT record contains the GO:0007409 IBD assertion at PTN000679673 with the same mouse/worm descendant sources. Mammalian SAD A/B deficiency disrupts axonal polarization in PMID:18268107, supporting this conserved biological role. The family evidence does not show an exclusive BRSK2 contribution, but there is no evidence of human BRSK2 loss of the inherited function.

Summary: Mouse Brsk2 provides a reasonable source for conserved axonogenesis.

Reason: Q69Z98 is reviewed mouse Brsk2. PMID:18268107 examines SAD A/B-deficient mouse neurons that fail normal axonal polarization, consistent with the transferred role. Preserve the ortholog annotation while recognizing that these combined-loss experiments do not resolve the individual contribution of each SAD kinase.

Summary: BRSK2 participates in kinase-dependent control of neuronal projections.

Reason: The Q69Z98 mouse Brsk2 transfer is consistent with the SAD-kinase neuronal-polarity phenotype and microtubule organization examined in PMID:18268107. The regulatory term appropriately describes a kinase acting on neuronal morphogenesis rather than constituting a structural neurite component.

Summary: Establishment of neuronal polarity is a conserved SAD-kinase function.

Reason: The actual PAINT IBD record at PTN000679673 supports GO:0030010 from mouse descendant evidence. PMID:18268107 demonstrates disrupted neuronal polarity and loss of asymmetric microtubule stabilization in SAD A/B-deficient neurons. The general cell-polarity term is supported without equating this evidence with epithelial planar polarity.

Summary: The mouse Brsk2 polarity transfer agrees with mammalian SAD-kinase biology.

Reason: Q69Z98 is the mouse Brsk2 source. The combined SAD A/B loss experiments in PMID:18268107 support a conserved role in establishing axon-dendrite polarity. The two raw curator/date versions of this assertion were deterministically collapsed during seeding; no source assertion is discarded during this review.

Summary: SAD-A/BRSK2 regulates actin organization in the pancreatic beta-cell setting.

Reason: PMID:22669945 reports SAD-A binding and phosphorylation of PAK1 and cytoskeletal remodeling in MIN6 beta cells. This is a supported context-specific consequence of the kinase pathway, not an intrinsic actin-binding or actin-polymerization activity of BRSK2. The abstract supports the cellular context but not every construct detail.

Summary: Neuronal differentiation is a broader developmental context for BRSK2 polarity signaling.

Reason: The mouse Brsk2 transfer is compatible with SAD-kinase-dependent neuronal morphogenesis in PMID:18268107. Retain the broader differentiation term as non-core because the best-defined mechanism concerns kinase-dependent polarity and projection organization, not all steps of neuronal differentiation.

Summary: BRSK2 contributes to a VCP-associated ERAD context.

Reason: The abstract reports VCP interaction and increased CD3-delta substrate abundance after endogenous BRSK2 depletion. This supports retaining the existing ERAD annotation, without assigning intrinsic proteolysis or a particular extraction step. Full Results were inaccessible.

Summary: Tau is a supported BRSK2 substrate and interaction context.

Reason: The tau review PMID:28386764 lists BRSK1/2 among tau-associated AMPK-related kinases; direct phosphorylation evidence is available in PMID:21985311. This supports substrate recognition, while the review does not establish a separate stable tau-binding scaffold activity. Keep the specific binding assertion as a non-core aspect of kinase-substrate engagement.

Summary: BRSK2 can localize to the perinuclear cytoplasmic region.

Reason: The UniProt subcellular-location mapping is independently supported by perinuclear colocalization of BRSK2 and Jab1 in PMID:22609399. This observed distribution is a context-dependent location, not a distinct core function or evidence of nuclear residence.

Summary: Tau phosphorylation is supported by the SAD-kinase phylogenetic assertion and human evidence.

Reason: The local PAINT file contains GO:0050321 at PTN000679673 with the seeded descendant sources, including human Q8IWQ3. That self-source is expected because human experimental tau-kinase evidence exists (PMID:21985311); it is not circular. The catalytic specificity fits the target's demonstrated activity.

Summary: BRSK2 directly phosphorylates tau.

Reason: PMID:21985311 explicitly includes brain-specific kinases 1 and 2 in assays of tau phosphorylation at S262/S356. The accessible abstract supports the enzymatic activity, while stronger cellular effects attributed to MARK1/SIK in that paper should not be assigned wholesale to BRSK2.

Summary: The Rhea/EC tau kinase mapping is experimentally corroborated.

Reason: The RHEA:12801/RHEA:53904 and EC:2.7.11.26 mapping specifies phosphotransfer to tau serine/threonine residues, consistent with the direct BRSK2-containing kinase assays in PMID:21985311. This is a supported catalytic activity rather than an untested generic family inference.

Summary: Mouse Brsk2 tau kinase activity transfers consistently to human BRSK2.

Reason: The Q69Z98 mouse ortholog assignment is consistent with the target's curated experimental tau-kinase annotation and the BRSK2 activity reported in PMID:21985311. The abstract identifies BRSK2 but does not specify the species of every assayed construct; no target-specific catalytic divergence is established.

Summary: The tau review's BRSK kinase assignment is supported by primary evidence.

Reason: PMID:28386764 is a secondary review that includes BRSK1/2 among tau kinases. Its assertion is corroborated by PMID:21985311, which explicitly assays the two brain-specific kinases. Retain the NAS annotation without treating the review itself as an independent experiment.

Summary: BRSK2 regulates axon formation through conserved SAD-kinase signaling.

Reason: The mouse Brsk2 source and the SAD A/B neuronal-polarization experiments in PMID:18268107 support regulation of axonogenesis. This kinase acts in a regulatory pathway, with the specific division of labor between the two SAD kinases unresolved by combined-loss experiments.

Summary: BRSK2 binding to the ATPase VCP/p97 is explicitly reported.

Reason: The abstract describes interaction with three VCP domains. This supports ATPase binding, without establishing modulation of ATP hydrolysis.

Summary: Direct regulation of ATP hydrolysis remains unverified.

Reason: GO:0060590 requires binding and modulation of ATP-hydrolysis activity. The accessible abstract establishes VCP interaction and an ERAD phenotype, but does not expose a hydrolysis assay. Full Results are needed to adjudicate this more specific molecular-function claim.

Summary: SAD-A/BRSK2 regulates glucose-stimulated insulin secretion in beta cells.

Reason: PMID:22669945 reports direct PAK1 binding/phosphorylation and PAK1-dependent enhancement of secretion, including MIN6 beta-cell experiments. The seeded term is direction-neutral and captures this kinase regulatory role. Do not generalize the stimulatory result to all BRSK2 phosphorylation states or all tissues; UniProt also records a distinct inhibitory CDK16-linked context.

Summary: The mouse Brsk2 insulin-secretion transfer describes a supported physiological context.

Reason: Q69Z98 is mouse Brsk2, and the beta-cell kinase mechanism in PMID:22669945 supports a role in glucose-responsive secretion. Retain the direction-neutral regulatory process as non-core; the evidence does not imply uniform stimulation by every BRSK2 form or activation state.

Summary: The accessible evidence favors a protective effect rather than a demonstrated apoptotic execution step.

Reason: The complete abstract reports increased ER-stress apoptosis after BRSK2 depletion and reduced apoptosis after either wild-type or kinase-dead overexpression. These observations point toward negative regulation, not an established catalytic death-signaling step. The full paper and listed corrigendum were not recovered, so retain uncertainty rather than remove the experimental annotation or confidently replace it. The kinase-dead result prevents asserting that the reported protection requires kinase activity.

Summary: The epithelial planar-polarity scope is not established by the neuronal evidence inspected.

Reason: The official GO definition/parent graph places GO:0090176 within establishment of planar polarity, with epithelial/tissue-polarity ancestry. PMID:18268107 instead examines axon-dendrite neuronal polarity and microtubule stability. Q69Z98 is the correct mouse Brsk2 ortholog, but its exact experimental chain for this more restrictive term was not recovered. Keep the source assertion unchanged and unresolved rather than equating all cell polarity with epithelial planar polarity.

Summary: BRSK2 catalyzes phosphorylation of protein serine residues.

Reason: The RHEA:17989 mapping agrees with tau serine phosphorylation attributed to BRSK2 in PMID:21985311. It is a valid catalytic subactivity of the broader serine/threonine kinase function, not a separate core unit.

Summary: The exact distal-axon localization evidence for the rat BRSK2 transfer remains uninspected.

Reason: The source accession D3ZML2 is rat BRSK2, confirmed by an official NCBI protein record. Neuronal projection function alone does not establish localization to the distal axon, and the exact donor localization experiment was not recovered. Preserve the ortholog assertion pending the relevant localization evidence, rather than infer a false transfer from this access gap.

Summary: The inferred retrotranslocation-regulation claim and current obsolete-term replacement remain unresolved.

Reason: VCP binding alone does not identify regulation of substrate extraction. Preserve the machine-sourced obsolete ID/label; current replacement metadata was inaccessible, and older ontology snapshots cannot settle it.

Summary: Specific retrotranslocation regulation remains unverified.

Reason: The abstract's CD3-delta abundance phenotype does not isolate retrotranslocation from other ERAD steps. Full Results and current replacement metadata for the machine-sourced obsolete term were unavailable.

Summary: Specific BRSK2 regulation of synaptic vesicle clustering remains insufficiently traced.

Reason: The ARBA assertion is plausible for the SAD-kinase family, but the inspected sources do not resolve target-specific clustering evidence. PMID:18268107 cites SAD-family synaptic work while experimentally studying neuronal polarity. Neither a BRSK2-specific clustering assay nor the exact ARBA source rule was inspected, so avoid either accepting a paralog-wide generalization or calling it false.

Summary: The cited neuronal-polarity paper does not itself resolve BRSK2-specific vesicle clustering.

Reason: PMID:18268107 mentions SAD-kinase presynaptic vesicle clustering through earlier literature, but its inspected experiments address microtubule stability and SAD A/B neuronal polarity. The cited antecedent clustering evidence was not fully traced to human BRSK2. Preserve this TAS source row pending that chain; do not remove it based on the title or a SAD-B-focused abstract.