ARBA00089176 response to lectin (GO:1990840)

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