ARBA00089180 cellular response to lectin (GO:1990858)

id: ARBA00089180
description: 'Rule predicts GO:1990858 "cellular response to lectin" based on two
  disjoint condition sets: (1) two serine/threonine protein kinase domains in Primates,
  and (2) two E1A binding protein p300 acetyltransferase domains in Catarrhini (Old
  World primates). Analysis reveals complete disjunction between condition sets (Jaccard=0.0),
  complete redundancy within condition set 2 (Jaccard=1.0), and very low coverage
  of the predicted GO term (3-40% containment, 3-4% Jaccard for all domain-GO pairs).'
status: COMPLETE
rule_type: ARBA
rule:
  rule_id: ARBA00089180
  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: Condition set 1 requires two serine/threonine protein kinase domains from
      different CATH superfamilies. Analysis shows 15 proteins match both domains,
      while 18 additional proteins match only the first domain (containment_b_in_a=1.0,
      indicating domain 3.30.200.20:FF:000069 is a strict subset of 1.10.510.10:FF:000011).
      This represents general kinase machinery, not lectin-specific signaling components.
    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: 'Condition set 2 requires two p300/CBP domains (KIX domain and bromodomain/acetyltransferase
      region). Analysis reveals complete redundancy: both domains co-occur in the
      exact same 5 proteins (Jaccard=1.0, containment=1.0 both directions). This identifies
      canonical p300/CBP proteins, which are general transcriptional coactivators
      functioning in hundreds of pathways beyond lectin signaling. The taxonomic restriction
      to Catarrhini (Old World primates) lacks biological justification given that
      p300 function is conserved broadly across mammals.'
    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:1990858
    go_label: cellular 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:1990858
      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:1990858
      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:1990858
      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:1990858
      containment: 0.2
      jaccard_similarity: 0.042
      intersection_count: 3
      exclusive_count: 12
review_summary: 'ARBA00089180 attempts to predict lectin response function by identifying
  proteins with general signaling domain architectures. The rule exhibits three critical
  flaws: (1) Complete redundancy in condition set 2 where two p300 domains always
  co-occur in the same 5 proteins, making one domain unnecessary; (2) Complete disjunction
  between condition sets, which combine unrelated protein families (kinases vs acetyltransferases)
  to predict the same specific function; and (3) Very poor GO term coverage, with
  only 3-40% containment and 3-4% Jaccard similarity between domains and the predicted
  GO term. While literature confirms that p300/CBP and certain kinases like Raf-1
  do participate in C-type lectin receptor signaling pathways, these proteins are
  multifunctional components operating in hundreds of cellular processes. The rule
  conflates participation in lectin signaling with being a lectin-response-specific
  protein, leading to systematic over-annotation. Domain architecture alone cannot
  distinguish lectin-specific functions from the myriad other roles these proteins
  execute.'
action: DEPRECATE
action_rationale: 'This rule should be deprecated due to fundamental design flaws
  that produce invalid annotations. The evidence demonstrates three irreconcilable
  problems: First, the complete redundancy in CS2 (Jaccard=1.0) indicates poor rule
  design where one domain provides no additional information beyond the other. Second,
  the complete disjunction between condition sets (Jaccard=0.0 for all cross-set domain
  pairs) reveals that the rule artificially combines unrelated protein families to
  predict a single specific function, violating biological coherence. Third, the extremely
  low GO term coverage (3-40% containment across all domain-GO pairs) demonstrates
  that the vast majority of proteins matching these domains do not actually have lectin
  response as their primary function. The deep research confirms that while p300/CBP
  and RAF1 kinase do participate in C-type lectin receptor signaling, they are general-purpose
  signaling machinery used in hundreds of pathways. Annotating all proteins with serine/threonine
  kinase domains or p300/CBP domains as having "cellular response to lectin" as their
  function fundamentally misrepresents their biological roles and creates false positives
  at scale. The appropriate annotations for these proteins would be their core molecular
  functions (e.g., "histone acetyltransferase activity" for p300, "protein serine/threonine
  kinase activity" for kinases) rather than pathway-specific process terms. This rule
  cannot be salvaged through modification because the fundamental logic of using general
  domain architecture to predict stimulus-specific responses is flawed for these particular
  multifunctional protein families.'
suggested_modifications: []
parsimony:
  assessment: OVERLY_COMPLEX
  notes: The rule demonstrates multiple layers of unnecessary complexity and poor
    design. In CS2, requiring both 1.10.246.20:FF:000001 (KIX domain) and 1.20.1020.10:FF:000001
    (bromodomain/acetyltransferase) provides no additional specificity since these
    domains co-occur in exactly the same 5 proteins (Jaccard=1.0). This is pure redundancy
    masquerading as specificity. In CS1, requiring both kinase domains provides only
    modest additional specificity (containment_b_in_a=1.0 indicates one domain is
    a strict subset of the other). The combination of two completely disjoint condition
    sets predicting the same narrow GO term violates parsimony principles by forcing
    unrelated protein families into a single functional category. A parsimonious rule
    would either (a) target proteins directly associated with lectin receptors through
    protein interaction data, or (b) acknowledge that these are general signaling
    components and annotate them with their core molecular functions rather than pathway-specific
    process terms.
  supported_by:
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-analysis.yaml
    supporting_text: '"condition_a: 1.10.246.20:FF:000001, condition_b: 1.20.1020.10:FF:000001,
      intersection_count: 5, jaccard_similarity: 1.0, containment_a_in_b: 1.0, containment_b_in_a:
      1.0, interpretation: REDUNDANT"'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-analysis.yaml
    supporting_text: '"condition_a: 1.10.510.10:FF:000011, condition_b: 1.10.246.20:FF:000001,
      intersection_count: 0, jaccard_similarity: 0.0, interpretation: DISJOINT"'
literature_support:
  assessment: CONTRADICTED
  notes: 'The deep research provides strong evidence that contradicts the rule''s
    logic. While the literature confirms that p300/CBP and RAF1 kinase participate
    in C-type lectin receptor signaling (DC-SIGN activates RAF1, which phosphorylates
    NF-κB p65 at Ser276, creating a binding site for p300/CBP acetyltransferase activity),
    the research explicitly identifies these proteins as multifunctional general signaling
    components, not lectin-specific effectors. The deep research states: "serine/threonine
    kinase domains and p300 acetyltransferase domains are multifunctional proteins
    operating across hundreds of cellular pathways beyond lectin signaling" and "Annotating
    all proteins with these domain signatures as responding to lectins fails to capture
    the specificity required by GO annotation standards." The literature documents
    that p300/CBP interact with approximately 400 different proteins and regulate
    responses to oxidative stress, hypoxia, growth factors, cytokines, and numerous
    other stimuli. The research concludes that "simply matching domain signatures
    cannot justify annotation with the specific functional term ''cellular response
    to lectin''" and that the rule "conflates involvement in lectin signaling with
    direct participation in lectin response processes." This represents a fundamental
    contradiction: the literature confirms participation but explicitly argues against
    the annotation strategy.'
  supported_by:
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"The fundamental issue is that the rule conflates involvement
      in lectin signaling with direct participation in lectin response processes.
      Serine/threonine kinase domains and p300 acetyltransferase domains are multifunctional
      proteins operating across hundreds of cellular pathways beyond lectin signaling.
      Annotating all proteins with these domain signatures as responding to lectins
      fails to capture the specificity required by GO annotation standards and would
      produce a substantial proportion of false positives."'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"p300 and CREB-binding protein (CBP) form a closely related
      family of transcriptional coactivators characterized by remarkable structural
      complexity and functional diversity. The functional breadth of p300/CBP extends
      far beyond any single pathway. These proteins interact with approximately 400
      different proteins, including numerous DNA-binding transcription factors and
      serve as coactivators for diverse cellular processes."'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"When DC-SIGN binds to mannose-carrying pathogens, it activates
      the serine/threonine kinase RAF1. RAF1 signaling leads to phosphorylation of
      NF-κB subunit p65 at serine 276, which creates a docking site that is recognized
      by CREB-binding protein and p300. The acetylation of p65 by p300/CBP enhances
      the transcriptional activity of p65 itself. However, this represents only one
      of hundreds of signaling contexts in which p300/CBP function."'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"Without additional information such as direct association with
      lectin receptors, upstream pattern recognition receptor scaffolds, or demonstrable
      involvement in lectin signaling cascades, the domain architecture alone cannot
      justify annotation with the specific functional term ''cellular response to
      lectin.''"'
condition_overlap:
  assessment: SIGNIFICANT
  notes: 'The rule exhibits two distinct forms of problematic overlap. Within condition
    set 2, there is complete redundancy: the two p300/CBP domains (1.10.246.20:FF:000001
    and 1.20.1020.10:FF:000001) co-occur in exactly the same 5 proteins with Jaccard=1.0
    and containment=1.0 in both directions. This means one of these domain requirements
    is entirely superfluous. Between the two condition sets, there is complete disjunction:
    the kinase domains in CS1 and the p300 domains in CS2 share zero proteins (Jaccard=0.0
    for all cross-set comparisons). This creates a logical incoherence where the rule
    uses an OR operation to combine two completely unrelated protein families (kinases
    and acetyltransferases) to predict the same specific biological process. This
    pattern suggests the rule was constructed by identifying proteins with known lectin-related
    annotations and then generalizing their domain signatures, without considering
    whether those domains are diagnostic for lectin response versus being general
    signaling components shared across many pathways.'
  supported_by:
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-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/ARBA00089180/ARBA00089180-analysis.yaml
    supporting_text: '"condition_a: 1.10.510.10:FF:000011, condition_b: 1.10.246.20:FF:000001,
      count_a: 33, count_b: 5, intersection_count: 0, jaccard_similarity: 0.0, interpretation:
      DISJOINT"'
go_specificity:
  assessment: MISMATCHED
  notes: 'The GO term "cellular response to lectin" (GO:1990858) is inappropriately
    specific for the proteins matched by this rule. The quantitative analysis demonstrates
    this mismatch clearly: domain 1.10.510.10:FF:000011 shows only 9% containment
    in GO:1990858 (3 of 33 proteins); domain 3.30.200.20:FF:000069 shows 20% containment
    (3 of 15 proteins); domains 1.10.246.20:FF:000001 and 1.20.1020.10:FF:000001 show
    40% containment (2 of 5 proteins). Jaccard similarities range from 3.2% to 4.2%.
    These metrics indicate that the vast majority of proteins with these domain architectures
    do not have lectin response as their primary or core function. The GO annotation
    standard requires that terms describe the actual function of the gene product.
    For p300/CBP, the appropriate terms would be "histone acetyltransferase activity"
    (GO:0004402) or "transcription coactivator activity" (GO:0003713). For serine/threonine
    kinases, the appropriate terms would be "protein serine/threonine kinase activity"
    (GO:0004674) or more specific kinase terms based on substrate specificity. Process
    terms like "cellular response to lectin" should be reserved for proteins whose
    primary role involves detecting or responding to lectin stimuli, not for general
    signaling machinery that happens to be employed downstream of lectin receptors
    among hundreds of other contexts.'
  supported_by:
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-analysis.yaml
    supporting_text: '"condition_a: 1.10.510.10:FF:000011, condition_b: GO:1990858,
      count_a: 33, count_b: 59, intersection_count: 3, jaccard_similarity: 0.033707865168539325,
      containment_a_in_b: 0.09090909090909091, interpretation: LOW"'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-analysis.yaml
    supporting_text: '"condition_a: 1.10.246.20:FF:000001, condition_b: GO:1990858,
      count_a: 5, count_b: 59, intersection_count: 2, jaccard_similarity: 0.03225806451612903,
      containment_a_in_b: 0.4, interpretation: LOW"'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"The GO annotation standard requires that terms describe the
      function of the specific gene product rather than every pathway in which that
      product participates. A protein that functions as a general transcriptional
      coactivator in hundreds of processes should not be annotated with every GO term
      representing those processes."'
taxonomic_scope:
  assessment: UNNECESSARY
  notes: 'The rule applies different taxonomic restrictions to the two condition sets:
    Primates (NCBITaxon:9443) for CS1 and Catarrhini (Old World primates, NCBITaxon:9526)
    for CS2. These restrictions appear arbitrary and lack biological justification.
    The deep research notes that "C-type lectin receptor signaling mechanisms show
    conservation across primates" and that "p300 acetyltransferase function and C-type
    lectin receptor signaling appear conserved across a broader range of primates."
    The functional domains of p300, including the KIX domain and acetyltransferase
    domain, are highly conserved across mammalian species. The restriction to Catarrhini
    for p300/CBP is particularly puzzling since there is no evidence that p300 function
    in lectin signaling is specific to Old World primates versus other primates or
    mammals. The deep research concludes: "If p300/CBP function in lectin signaling
    is conserved across primates (as the evidence suggests), the taxonomic restriction
    appears unjustified." However, given that the entire rule should be deprecated,
    the taxonomic scope issue is secondary to the more fundamental problem that these
    domain architectures do not validly predict lectin response function in any taxon.'
  supported_by:
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"C-type lectin receptor signaling mechanisms show conservation
      across primates, suggesting that if the rule were valid for one primate species,
      it would likely apply broadly across primates. A genome-wide study comparing
      immune responses in humans, chimpanzees, and rhesus macaques found that ''core''
      immune responses that are critical to fight any invading pathogen are the most
      conserved across primates."'
  - reference_id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
    supporting_text: '"The restriction of the p300/CBP condition to Catarrhini (Old
      World primates) is puzzling. p300 acetyltransferase function and C-type lectin
      receptor signaling appear conserved across a broader range of primates. The
      functional domains of p300, including the KIX domain and acetyltransferase domain,
      are highly conserved across mammalian species."'
confidence: 0.95
references:
- id: file:rules/arba/ARBA00089180/ARBA00089180-deep-research-perplexity.md
  title: Deep research analysis of ARBA00089180 rule validity
  findings:
  - statement: p300/CBP and RAF1 participate in C-type lectin receptor signaling but
      are multifunctional general signaling components, not lectin- specific effectors
  - statement: Domain architecture alone cannot justify annotation with "cellular
      response to lectin" for these general signaling proteins
  - statement: The rule conflates participation in lectin signaling with being a lectin-response-specific
      protein, leading to false positives
- id: file:rules/arba/ARBA00089180/ARBA00089180-analysis.yaml
  title: Quantitative overlap analysis of ARBA00089180 domains
  findings:
  - statement: Condition set 2 shows complete redundancy with Jaccard=1.0 for both
      p300 domains
  - statement: Condition sets are completely disjoint with Jaccard=0.0 for all cross-set
      domain pairs
  - statement: All domain-GO pairs show very low coverage (3-40% containment, 3-4%
      Jaccard similarity)