id: ARBA00089176 description: This rule predicts GO:1990840 (response to lectin) for primate proteins using two distinct condition sets. Condition set 1 requires non-specific serine/threonine protein kinase domains (FunFams 1.10.510.10:FF:000011 and 3.30.200.20:FF:000069) in Primates (NCBITaxon:9443). Condition set 2 requires E1A binding protein p300 domains (FunFams 1.10.246.20:FF:000001 and 1.20.1020.10:FF:000001) in Catarrhini (NCBITaxon:9526, Old World monkeys and apes). status: COMPLETE rule_type: ARBA rule: rule_id: ARBA00089176 condition_sets: - number: 1 conditions: - condition_type: FUNFAM value: 1.10.510.10:FF:000011 curie: CATH.FunFam:1.10.510.10:FF:000011 label: Non-specific serine/threonine protein kinase negated: false - condition_type: FUNFAM value: 3.30.200.20:FF:000069 curie: CATH.FunFam:3.30.200.20:FF:000069 label: Non-specific serine/threonine protein kinase negated: false - condition_type: TAXON value: '9443' curie: NCBITaxon:9443 label: Primates negated: false notes: This condition set targets non-specific serine/threonine kinases in primates. The two FunFam domains show moderate overlap (Jaccard 0.45), with domain 3.30.200.20:FF:000069 being completely contained within 1.10.510.10:FF:000011 (15 proteins vs 33 proteins). Only 3 of 33 proteins with the first domain are annotated with GO:1990840, suggesting low predictive power (9% containment). pairwise_overlap: - condition_a: 1.10.510.10:FF:000011 condition_b: 3.30.200.20:FF:000069 protein_database: SWISSPROT count_a: 33 count_b: 15 intersection_count: 15 a_minus_b_count: 18 b_minus_a_count: 0 jaccard_similarity: 0.45454545454545453 containment_a_in_b: 0.45454545454545453 containment_b_in_a: 1.0 interpretation: SUBSET - number: 2 conditions: - condition_type: FUNFAM value: 1.10.246.20:FF:000001 curie: CATH.FunFam:1.10.246.20:FF:000001 label: E1A binding protein p300 negated: false - condition_type: FUNFAM value: 1.20.1020.10:FF:000001 curie: CATH.FunFam:1.20.1020.10:FF:000001 label: E1A binding protein p300 negated: false - condition_type: TAXON value: '9526' curie: NCBITaxon:9526 label: Catarrhini negated: false notes: This condition set targets p300/CBP proteins in Catarrhini (Old World primates). The two FunFam domains are completely redundant (Jaccard 1.0), both matching exactly 5 proteins. Only 2 of these 5 proteins are annotated with GO:1990840 (40% containment), indicating modest predictive power. The two condition sets are completely disjoint from each other (no protein overlap). pairwise_overlap: - condition_a: 1.10.246.20:FF:000001 condition_b: 1.20.1020.10:FF:000001 protein_database: SWISSPROT count_a: 5 count_b: 5 intersection_count: 5 a_minus_b_count: 0 b_minus_a_count: 0 jaccard_similarity: 1.0 containment_a_in_b: 1.0 containment_b_in_a: 1.0 interpretation: REDUNDANT go_annotations: - go_id: GO:1990840 go_label: response to lectin aspect: BP entries: - id: 1.10.246.20:FF:000001 type: FUNFAM label: E1A binding protein p300 appears_in_condition_sets: - 2 protein_count: 5 related_entries: - relationship: EQUIV target_id: 1.10.510.10:FF:000011 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 5 - relationship: EQUIV target_id: 3.30.200.20:FF:000069 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 5 - relationship: EQUIV target_id: 1.20.1020.10:FF:000001 containment: 1.0 jaccard_similarity: 1.0 intersection_count: 5 exclusive_count: 0 - relationship: PREDICTS target_id: GO:1990840 containment: 0.4 jaccard_similarity: 0.032 intersection_count: 2 exclusive_count: 3 - id: 1.10.510.10:FF:000011 type: FUNFAM label: Non-specific serine/threonine protein kinase appears_in_condition_sets: - 1 protein_count: 33 related_entries: - relationship: PREDICTED_BY target_id: 3.30.200.20:FF:000069 containment: 1.0 jaccard_similarity: 0.455 intersection_count: 15 exclusive_count: 0 - relationship: EQUIV target_id: 1.10.246.20:FF:000001 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 33 - relationship: EQUIV target_id: 1.20.1020.10:FF:000001 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 33 - relationship: PREDICTS target_id: GO:1990840 containment: 0.091 jaccard_similarity: 0.034 intersection_count: 3 exclusive_count: 30 - id: 1.20.1020.10:FF:000001 type: FUNFAM label: E1A binding protein p300 appears_in_condition_sets: - 2 protein_count: 5 related_entries: - relationship: EQUIV target_id: 1.10.510.10:FF:000011 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 5 - relationship: EQUIV target_id: 3.30.200.20:FF:000069 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 5 - relationship: EQUIV target_id: 1.10.246.20:FF:000001 containment: 1.0 jaccard_similarity: 1.0 intersection_count: 5 exclusive_count: 0 - relationship: PREDICTS target_id: GO:1990840 containment: 0.4 jaccard_similarity: 0.032 intersection_count: 2 exclusive_count: 3 - id: 3.30.200.20:FF:000069 type: FUNFAM label: Non-specific serine/threonine protein kinase appears_in_condition_sets: - 1 protein_count: 15 related_entries: - relationship: PREDICTS target_id: 1.10.510.10:FF:000011 containment: 0.455 jaccard_similarity: 0.455 intersection_count: 15 exclusive_count: 18 - relationship: EQUIV target_id: 1.10.246.20:FF:000001 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 15 - relationship: EQUIV target_id: 1.20.1020.10:FF:000001 containment: 0.0 jaccard_similarity: 0.0 intersection_count: 0 exclusive_count: 15 - relationship: PREDICTS target_id: GO:1990840 containment: 0.2 jaccard_similarity: 0.042 intersection_count: 3 exclusive_count: 12 review_summary: 'ARBA00089176 predicts "response to lectin" for two mechanistically distinct protein families in primates: serine/threonine kinases and p300/CBP histone acetyltransferases. The rule shows multiple concerning features: (1) very low overlap between domain conditions and existing GO:1990840 annotations (3-9% for kinases, 3-40% for p300), suggesting poor predictive accuracy; (2) complete redundancy in condition set 2 (Jaccard 1.0 for p300 domains); (3) lack of obvious mechanistic connection between these two protein families and lectin response; (4) questionable taxonomic specificity to primates/Catarrhini for what might be a conserved cellular response. The biological rationale for this rule is unclear and requires deep research validation to determine if there is experimental evidence linking these specific protein families to lectin response pathways.' action: DEPRECATE action_rationale: This rule should be deprecated due to fundamental design flaws that create unacceptably high false positive risk. While deep research confirms that RAF1 and p300 do participate in DC-SIGN-mediated lectin signaling, the generic domain signatures used are not diagnostic for lectin responsiveness. Both serine/threonine kinase and p300 domains are shared by hundreds of proteins across diverse signaling pathways. The very low overlap with existing GO:1990840 annotations (3-40%) empirically validates this concern. Additionally, the primate/Catarrhini taxonomic restrictions are unjustified given the conservation of lectin response pathways across mammals. The rule conflates downstream effectors with pathway-specific components. A properly designed lectin response rule would require lectin-receptor or pathway-proximal signatures (CTLD domains, Syk-binding motifs, CARD9/BCL10/MALT1 domains) rather than generic effectors that participate in many immune and signaling pathways. suggested_modifications: - Redesign rule to require lectin-receptor signatures (CTLD domains) or pathway-proximal adaptors (Syk-binding motifs, CARD9/BCL10/MALT1 domains) instead of generic downstream effectors - If downstream kinases must be included, add co-occurrence requirements with CLR pathway components to establish pathway context - Remove primate/Catarrhini taxonomic restrictions and expand to Mammalia or Vertebrata given pathway conservation - Remove redundant p300 domain condition (either 1.10.246.20:FF:000001 or 1.20.1020.10:FF:000001) as they show complete overlap - Consider alternative GO terms such as "regulation of NF-kappaB signaling" or "innate immune response" for proteins matching only generic kinase/p300 domains without CLR pathway context parsimony: assessment: OVERLY_COMPLEX notes: The rule combines two completely disjoint condition sets targeting unrelated protein families (kinases vs acetyltransferases) with no mechanistic unity beyond both potentially participating in downstream lectin signaling. Condition set 2 also shows complete internal redundancy (Jaccard 1.0 for p300 domains). This complexity is not justified by biological necessity. If lectin-specific annotation is desired, a more parsimonious approach would require lectin-receptor or pathway-proximal signatures (CTLD, Syk motifs, CARD9 domains) rather than generic downstream effectors. The current design creates unnecessary complexity and false positive risk. supported_by: - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-analysis.yaml supporting_text: '"condition_a: 1.10.246.20:FF:000001, condition_b: 1.20.1020.10:FF:000001, protein_database: SWISSPROT, count_a: 5, count_b: 5, intersection_count: 5, a_minus_b_count: 0, b_minus_a_count: 0, jaccard_similarity: 1.0, containment_a_in_b: 1.0, containment_b_in_a: 1.0, interpretation: REDUNDANT"' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-falcon.md supporting_text: '"Strengthen rule logic by requiring lectin-receptor or adaptor/kinase signatures proximal to CLR signaling, e.g., presence of CTLD consistent with mammalian CLR families, Syk-binding motifs, CARD9/BCL10/MALT1 association domains, or complement lectin pathway PRM/MASP signatures. This would markedly reduce false positives."' literature_support: assessment: WEAK notes: Deep research reveals that lectin responses in mammals are mediated by C-type lectin receptors (CLRs) including DC-SIGN and Dectin-1, which signal through Syk and CARD9 pathways. There is specific evidence that DC-SIGN triggers RAF1 (a serine/threonine kinase) activation, which leads to p300-mediated acetylation of NF-kappaB p65. However, the rule targets generic "non-specific serine/threonine kinase" and "p300" domains that are shared by hundreds of proteins across diverse signaling pathways. The literature shows these molecules can participate in lectin signaling, but their domain presence is not diagnostic for lectin responsiveness. Both Perplexity and Falcon research emphasize that these domains are multifunctional and widely reused, creating high false positive risk. The low overlap with existing GO:1990840 annotations (3-40%) supports this concern. supported_by: - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-perplexity.md supporting_text: '"When DC-SIGN, a C-type lectin receptor expressed on dendritic cells, binds to mannose-carrying pathogens including Mycobacterium tuberculosis, HIV-1, and Candida albicans, it induces an intracellular signaling cascade with RAF1 as the central component."' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-perplexity.md supporting_text: '"RFC1-dependent acetylation of p65 at Ser276 increases the transcriptional activity of p65 itself. The experimental evidence for p300 involvement is particularly strong."' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-perplexity.md supporting_text: '"The serine/threonine kinase domains specified (CATH.FunFam:1.10.510.10:FF:000011 and 3.30.200.20:FF:000069) are shared by hundreds of kinases serving diverse biological functions. RAF1 is one of three RAF family members (RAF1, BRAF, KRAF2), and other kinases containing these domains participate in growth factor signaling, stress responses, immune activation, and metabolic regulation—often without any connection to lectin signaling."' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-falcon.md supporting_text: '"Generic serine/threonine kinase domains and p300/CBP histone acetyltransferase domains are not diagnostic for lectin responsiveness and occur across many signaling pathways. The rule therefore risks false positives and appears biologically under-justified, particularly with primate-restricted taxon filters."' condition_overlap: assessment: SIGNIFICANT notes: Within condition set 2, there is complete overlap (REDUNDANT) between the two p300 domains. Between the two condition sets, there is complete separation (DISJOINT) with no protein overlap, indicating they target entirely different protein families. The moderate overlap within condition set 1 (Jaccard 0.45) suggests some but not complete redundancy between the two kinase domains. Overall, the rule shows inefficient condition design with unnecessary duplication in one set and questionable unification of disjoint protein families under a single GO annotation. supported_by: - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-analysis.yaml supporting_text: '"Analyzed 6 domain-domain pairs and 4 domain-GO pairs across entire rule. Average Jaccard similarity: 0.160. 1 pairs with >50% overlap, 1 subset relationships."' go_specificity: assessment: TOO_BROAD notes: GO:1990840 "response to lectin" is an appropriate term for proteins directly involved in lectin recognition and signaling. Deep research confirms this term is used in recent human datasets (NAFLD, AMI, sepsis transcriptomics). However, applying it based solely on generic kinase or p300 domains is too broad. The term should be reserved for proteins with lectin-receptor or adaptor signatures proximal to CLR signaling (e.g., CTLD domains, Syk-binding motifs, CARD9/BCL10/ MALT1 domains). Generic serine/threonine kinases and p300 are downstream effectors that participate in many signaling pathways. More appropriate terms for proteins matching only these domains would be "regulation of NF-kappaB signaling" or "innate immune response" when additional evidence links them to PRR contexts. supported_by: - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-falcon.md supporting_text: '"Retain the term for proteins with domain signatures or orthology to lectin receptors (e.g., CLRs with CTLD and signaling motifs/adaptors) or complement lectin pathway components (MBL, ficolins, MASPs)."' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-perplexity.md supporting_text: '"The appropriateness of GO:1990840 versus these alternatives depends on whether the annotation should capture the immediate molecular mechanism (p300''s acetyltransferase activity) or the integrated cellular response context (DC-SIGN-mediated recognition of pathogenic lectins)."' taxonomic_scope: assessment: TOO_NARROW notes: The rule restricts condition set 1 to Primates and condition set 2 to Catarrhini, which is inappropriately narrow for mammalian lectin response pathways. Deep research confirms that CLR signaling (Dectin-1, DC-SIGN) and complement lectin pathways are broadly conserved across vertebrates. Studies in both humans and mice document conserved CLR-triggered signaling through Syk, CARD9, and downstream kinases. The restriction to primates/catarrhines appears to reflect annotation database biases rather than biological differences. If this rule were to be retained (which is not recommended), the taxonomic scope should expand to Mammalia or Vertebrata, as the core lectin response mechanisms are not primate-specific. supported_by: - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-perplexity.md supporting_text: '"Despite these species differences, the core DC-SIGN-RAF1-p300 pathway appears fundamentally conserved across primates and even across mammals more broadly. RAF1, dectin-1, and p300 are present in all these organisms with high sequence conservation in their catalytic domains."' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-falcon.md supporting_text: '"Remove or relax primate/Catarrhini taxon restrictions unless supported by evidence of lineage-specific lectin pathways or ligands; mammalian lectin responses are broadly conserved and not primate-specific."' - reference_id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-falcon.md supporting_text: '"2024 reviews emphasize the conserved genomic organization and function of Dectin clusters in humans and mice, documenting CLR-triggered phagocytosis, cytokine production, ROS/NETs, and antigen presentation."' confidence: 0.25 references: - id: file:rules/arba/ARBA00089176/ARBA00089176-analysis.yaml title: Domain overlap analysis for ARBA00089176 findings: - statement: Condition set 2 shows complete redundancy (Jaccard 1.0) between p300 domains - statement: Very low overlap between domains and GO:1990840 (3-9% for kinases, 3-40% for p300) - statement: Two condition sets are completely disjoint with no protein overlap - id: file:rules/arba/ARBA00089176/ARBA00089176.enriched.json title: Enriched rule data for ARBA00089176 findings: - statement: Rule created 2025-03-21, predicts GO:1990840 for Primates/Catarrhini - statement: Uses two condition sets targeting kinases and p300 proteins - id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-perplexity.md title: Deep research on lectin response pathways and kinase/p300 involvement (Perplexity) findings: - statement: DC-SIGN CLR triggers RAF1 kinase activation leading to p300-mediated NF-kappaB acetylation - statement: Generic serine/threonine kinase domains shared by hundreds of proteins in diverse pathways - statement: p300 participates in hundreds of biological processes beyond lectin signaling - statement: Core DC-SIGN-RAF1-p300 pathway conserved across mammals, not primate-specific - statement: Rule requires upstream CLR context or pathway-specific markers to avoid false positives - id: file:rules/arba/ARBA00089176/ARBA00089176-deep-research-falcon.md title: Deep research on CLR signaling and domain diagnosticity (Falcon) findings: - statement: CLR pathways signal via Syk/CARD9 with downstream serine/threonine kinases and p300 - statement: Non-specific kinase and p300 domains are not diagnostic for lectin responsiveness - statement: Recommendation to restrict annotation to proteins with CTLD or pathway-proximal signatures - statement: Primate/Catarrhini restrictions unjustified as lectin responses broadly conserved in mammals - statement: Term "response to lectin" used in recent human datasets but requires pathway context - id: https://www.informatics.jax.org/vocab/gene_ontology/GO:1990840 title: MGI Gene Ontology entry for GO:1990840 response to lectin findings: - statement: Describes cellular responses resulting from lectin stimulus