id: P27352
gene_symbol: CBLIF
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CBLIF (gastric intrinsic factor, GIF; also called intrinsic factor, IF) is a secreted
  cobalamin (vitamin B12)-binding glycoprotein produced by gastric parietal cells (and,
  at the margins of gastric anatomical regions, by some chief and enteroendocrine cells).
  Its principal role is the intestinal absorption of dietary cobalamin: after cobalamin is
  released from salivary/gastric haptocorrin in the proximal small intestine, CBLIF binds
  it tightly, and the resulting CBLIF-cobalamin complex is recognized in the distal ileum
  by the cubam receptor formed by cubilin (CUBN) and amnionless (AMN). Cubam mediates
  receptor-dependent endocytosis of the complex, which is then delivered to lysosomes where
  cobalamin is released for cellular use. Structurally CBLIF is a two-domain alpha6/alpha6
  barrel protein that binds one cobalamin at the domain interface in a base-on conformation.
  It is not an enzyme; it functions as a cobalamin-binding carrier and as the ligand
  recognized by the cubam cargo receptor. Loss-of-function mutations cause hereditary
  intrinsic factor deficiency (congenital/juvenile pernicious anemia; MIM:261000), a form of
  megaloblastic anemia resulting from vitamin B12 malabsorption.
alternative_products:
- name: '1'
  id: P27352-1
- name: '2'
  id: P27352-2
  sequence_note: VSP_041585
existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing CBLIF in the extracellular region. CBLIF is a
      secreted protein that acts extracellularly (in the gut lumen / on the intestinal
      apical surface) to bind and deliver cobalamin, so this is correct and part of the
      core biology.
    action: ACCEPT
    reason: >-
      UniProt records the protein as secreted, and it functions extracellularly as a
      cobalamin carrier. The IBA call is consistent with experimental localization and the
      known biology.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to cobalamin transport. CBLIF is required for intestinal
      absorption of dietary cobalamin, binding it and mediating cubam(CUBN/AMN)-dependent
      uptake in the ileum. This is a core biological process for the gene.
    action: ACCEPT
    reason: >-
      Supported experimentally by human loss-of-function disease (hereditary IF deficiency)
      and by the well-established IF-cobalamin/cubam absorption pathway. Correct and core.
    supported_by:
    - reference_id: PMID:20237569
      supporting_text: >-
        This occurs by the combined action of the gastric intrinsic factor (IF) and the
        ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin
        and the 45-kDa transmembrane protein amnionless.
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: >-
        Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After
        interaction with CUBN, the CBLIF-cobalamin complex is internalized via
        receptor-mediated endocytosis.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to cobalamin binding, the defining molecular function of
      CBLIF. This is directly supported by the crystal structure of the human IF-cobalamin
      complex and by defined cobalamin-contacting residues in UniProt.
    action: ACCEPT
    reason: >-
      Cobalamin binding is the core molecular function of intrinsic factor, confirmed by
      structural and biochemical evidence. The IBA call is at the correct level of
      specificity.
    supported_by:
    - reference_id: PMID:17954916
      supporting_text: >-
        the Cbl is bound at the interface of the domains in a base-on conformation
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to extracellular region derived from the UniProt "Secreted"
      subcellular location keyword mapping. Consistent with the experimental and
      phylogenetic evidence for a secreted protein.
    action: ACCEPT
    reason: >-
      Redundant with the IBA/IDA extracellular-region calls but correct; the SubCell mapping
      accurately reflects the secreted nature of the protein.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation (IPR002157, cobalamin-binding protein) to cobalamin
      transport. Consistent with the experimentally supported transport role.
    action: ACCEPT
    reason: >-
      The InterPro family mapping is biologically appropriate for CBLIF and matches the
      experimental IMP/IBA/TAS annotations to the same process.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: >-
        Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation (IPR002157) to cobalamin binding. Matches the
      structurally validated core molecular function.
    action: ACCEPT
    reason: >-
      The cobalamin-binding domain assignment is correct for CBLIF and the mapped MF term is
      the defining function, corroborated by crystallography (PMID:17954916).
    supported_by:
    - reference_id: PMID:17954916
      supporting_text: >-
        The structure of intrinsic factor (IF) in complex with cobalamin (Cbl) was
        determined at 2.6-A resolution.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20237569
  qualifier: enables
  review:
    summary: >-
      IPI annotation to the generic term protein binding, capturing the interaction with
      cubilin (CUBN, IntAct O60494). This interaction is real and functionally central (the
      IF-Cbl complex is recognized by the CUBN/AMN cubam receptor for ileal uptake), and is
      structurally defined. However, the bare "protein binding" term is uninformative about
      the actual function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidance, the uninformative "protein binding" term should not be treated
      as a core function even though the underlying CUBN interaction is genuine. The
      functional content of this interaction is better represented by the
      cobalamin-transport process and the cargo receptor ligand activity annotations, and by
      the specific CUBN partner recorded in UniProt SUBUNIT.
    supported_by:
    - reference_id: PMID:20237569
      supporting_text: >-
        how two distant CUB domains embrace the Cbl molecule by binding the two IF domains
        in a Ca(2+)-dependent manner
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "Interacts with CUBN (via CUB domains)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IPI annotation to protein binding from the HuRI high-throughput binary (yeast
      two-hybrid) interactome screen. The recorded partners (FFAR2, SLC13A4, SLC22A23,
      SLC7A1, SLC7A14, TMEM237) are membrane transporters/GPCRs with no established
      biological relationship to a secreted cobalamin-binding protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These are uninformative large-scale screen hits and the bare "protein binding" term
      conveys no functional information; they are very unlikely to reflect physiological
      partners of a secreted extracellular Cbl carrier. Marked as over-annotated rather than
      removed, per policy for IPI protein-binding annotations.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        reference interactome map of human binary protein interactions
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9758881
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS annotation to cobalamin transport, from the "Uptake of dietary cobalamins
      into enterocytes" pathway. CBLIF binds dietary cobalamin and delivers it to the ileal
      cubam receptor for absorption; this is the core process.
    action: ACCEPT
    reason: >-
      Reactome's pathway representation accurately captures CBLIF's role in the intestinal
      cobalamin absorption pathway, consistent with experimental (IMP) and phylogenetic
      (IBA) annotations.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: >-
        Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum.
- term:
    id: GO:0140355
    label: cargo receptor ligand activity
  evidence_type: EXP
  original_reference_id: PMID:17954916
  qualifier: enables
  review:
    summary: >-
      Experimental annotation to cargo receptor ligand activity. The cobalamin-loaded CBLIF
      complex is the ligand recognized by the cubam (CUBN/AMN) cargo receptor, which then
      internalizes it by endocytosis in the ileum. This captures the receptor-recognition
      facet of CBLIF's transport function.
    action: ACCEPT
    reason: >-
      Structural work shows CUBN recognizes the Cbl-saturated IF complex, and the complex is
      taken up by receptor-mediated endocytosis; "cargo receptor ligand activity" is the
      appropriate MF for a secreted carrier ligand that engages an endocytic receptor. This
      is an informative, core molecular function.
    supported_by:
    - reference_id: PMID:17954916
      supporting_text: >-
        CUB recognizes both the full-length Cbl-saturated IF complex and the Cbl-saturated
        cleaved IF complex but not the isolated
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: >-
        After interaction with CUBN, the CBLIF-cobalamin complex is internalized via
        receptor-mediated endocytosis.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000103
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to extracellular region for the reaction in which the cubam
      (CUBN:AMN) receptor binds the secreted CBLIF:RCbl complex. Correct for a secreted
      protein acting on the intestinal luminal/apical surface.
    action: ACCEPT
    reason: >-
      Consistent with the secreted subcellular location and with the other extracellular
      annotations.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000120
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to extracellular region for the reaction "CBLIF binds RCbl"
      (binding of free cobalamin by secreted intrinsic factor in the intestinal lumen).
      Correct for the secreted protein.
    action: ACCEPT
    reason: >-
      Redundant with other extracellular-region calls but accurate; the binding of cobalamin
      by CBLIF occurs extracellularly in the gut lumen.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000137
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to extracellular region for the cubam-mediated uptake
      reaction. Correct for the secreted CBLIF:RCbl complex engaging the cell-surface
      receptor prior to internalization.
    action: ACCEPT
    reason: >-
      Consistent with the secreted nature of the protein and its extracellular site of
      action.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3296462
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to extracellular region for the disease reaction "Defective
      CUBN does not transport GIF:Cbl". The extracellular localization of CBLIF is correct
      regardless of the disease context.
    action: ACCEPT
    reason: >-
      Accurate secreted localization; redundant with the other extracellular annotations.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3296477
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to extracellular region for the disease reaction "Defective
      AMN does not transport GIF:Cbl". The secreted CBLIF localization is correct.
    action: ACCEPT
    reason: >-
      Accurate secreted localization; redundant with the other extracellular annotations.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3315455
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to extracellular region for the disease reaction "Defective
      CBLIF does not bind Cbl". The secreted CBLIF localization is correct.
    action: ACCEPT
    reason: >-
      Accurate secreted localization; redundant with the other extracellular annotations.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000137
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to lysosomal lumen. After cubam-mediated endocytosis in the
      ileal enterocyte, the CBLIF:RCbl complex is delivered to lysosomes, where cobalamin is
      released and CBLIF is degraded. This is a genuine trafficking endpoint but not the
      protein's core (secreted, cobalamin-binding) function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The lysosomal-lumen localization reflects the fate of the internalized complex in the
      target enterocyte rather than where CBLIF performs its defining function; retain as a
      correct but non-core localization.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: >-
        After interaction with CUBN, the CBLIF-cobalamin complex is internalized via
        receptor-mediated endocytosis.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000243
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to lysosomal lumen for the reaction in which a lysosomal
      protease degrades CBLIF:RCbl to release cobalamin. Same non-core trafficking endpoint
      as R-HSA-3000137.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct localization of the internalized complex within the enterocyte lysosome, but
      peripheral to CBLIF's defining secreted cobalamin-binding function.
    supported_by:
    - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
      supporting_text: >-
        After interaction with CUBN, the CBLIF-cobalamin complex is internalized via
        receptor-mediated endocytosis.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:14695536
  qualifier: located_in
  review:
    summary: >-
      IDA localization to extracellular region. Recombinant CBLIF expressed in COS-7 cells
      was secreted with size, secretion rate, and pepsin sensitivity similar to native IF,
      supporting the secreted/extracellular localization.
    action: ACCEPT
    reason: >-
      Direct experimental support for secretion of the protein; core extracellular
      localization.
    supported_by:
    - reference_id: PMID:14695536
      supporting_text: >-
        The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the
        expressed IF were similar to native IF.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IDA
  original_reference_id: PMID:8886952
  qualifier: located_in
  review:
    summary: >-
      IDA localization to endosome, from immunoelectron microscopy of human gastric mucosa
      showing highest intrinsic factor antigen density on endocytic (and apical) membranes
      of parietal cells. Reflects the intracellular biosynthetic/secretory and endocytic
      compartments in the producing cell rather than the core secreted function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A real, experimentally observed localization within intrinsic-factor-producing cells,
      but peripheral to the protein's defining extracellular cobalamin-binding/transport
      role.
    supported_by:
    - reference_id: PMID:8886952
      supporting_text: >-
        Immunoelectron microscopy demonstrated the highest antigen density on endocytic and
        apical membranes of parietal cells.
- term:
    id: GO:0005902
    label: microvillus
  evidence_type: IDA
  original_reference_id: PMID:8886952
  qualifier: located_in
  review:
    summary: >-
      IDA localization to microvillus, from the same immuno-localization study of intrinsic
      factor in gastric mucosa. Represents cell-surface/apical membrane localization in the
      producing parietal cell; non-core relative to the secreted function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally observed apical/microvillar membrane association in parietal cells;
      correct but peripheral to CBLIF's core secreted cobalamin-binding/transport function.
    supported_by:
    - reference_id: PMID:8886952
      supporting_text: >-
        Immunoelectron microscopy demonstrated the highest antigen density on endocytic and
        apical membranes of parietal cells.
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IMP
  original_reference_id: PMID:15738392
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to cobalamin transport based on human genetics: biallelic nonsense and
      missense GIF (CBLIF) mutations cause hereditary intrinsic factor deficiency with
      juvenile megaloblastic anemia due to intestinal cobalamin malabsorption. This is the
      strongest experimental support for CBLIF's role in cobalamin transport/absorption.
    action: ACCEPT
    reason: >-
      Loss-of-function mutations abolishing intestinal cobalamin absorption directly
      demonstrate CBLIF's requirement for cobalamin transport; core process.
    supported_by:
    - reference_id: PMID:15738392
      supporting_text: >-
        harbored homozygous nonsense and missense mutations in these four families and in
        three additional families. The disease in these cases therefore should be classified
        as hereditary IF deficiency.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:8886952
  qualifier: located_in
  review:
    summary: >-
      IDA localization to apical plasma membrane, from immunoelectron microscopy showing
      highest intrinsic factor antigen density on apical (and endocytic) membranes of gastric
      parietal cells. Reflects the apical secretory surface of the producing cell.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported apical membrane association in parietal cells; a correct but
      non-core localization relative to the secreted extracellular function.
    supported_by:
    - reference_id: PMID:8886952
      supporting_text: >-
        Immunoelectron microscopy demonstrated the highest antigen density on endocytic and
        apical membranes of parietal cells.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IDA
  original_reference_id: PMID:14695536
  qualifier: enables
  review:
    summary: >-
      IDA annotation to cobalamin binding, the defining molecular function of CBLIF, assessed
      for recombinant IF (studied in the context of the congenital IF deficiency-associated
      Q23R variant). Directly corroborated by the crystal structure of the IF-cobalamin
      complex.
    action: ACCEPT
    reason: >-
      Cobalamin binding is CBLIF's core molecular function, supported here by direct assay of
      the recombinant protein and by structural evidence (PMID:17954916).
    supported_by:
    - reference_id: PMID:14695536
      supporting_text: >-
        The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the
        expressed IF were similar to native IF.
    - reference_id: PMID:17954916
      supporting_text: >-
        the Cbl is bound at the interface of the domains in a base-on conformation
core_functions:
- description: >-
    Binds dietary cobalamin (vitamin B12) as a secreted carrier and functions as the ligand
    recognized by the ileal cubam (CUBN/AMN) cargo receptor, thereby mediating
    receptor-dependent intestinal absorption of cobalamin.
  molecular_function:
    id: GO:0031419
    label: cobalamin binding
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:17954916
    supporting_text: >-
      the Cbl is bound at the interface of the domains in a base-on conformation
  - reference_id: PMID:15738392
    supporting_text: >-
      harbored homozygous nonsense and missense mutations in these four families and in
      three additional families. The disease in these cases therefore should be classified
      as hereditary IF deficiency.
  - reference_id: file:human/CBLIF/CBLIF-uniprot.txt
    supporting_text: >-
      Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After
      interaction with CUBN, the CBLIF-cobalamin complex is internalized via
      receptor-mediated endocytosis.
- description: >-
    Acts as the cargo ligand for the ileal endocytic cubam receptor: the cobalamin-loaded
    CBLIF complex is recognized by CUBN/AMN and internalized by receptor-mediated
    endocytosis, coupling cobalamin binding to its cellular uptake.
  molecular_function:
    id: GO:0140355
    label: cargo receptor ligand activity
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:20237569
    supporting_text: >-
      This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal
      endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin and the
      45-kDa transmembrane protein amnionless.
  - reference_id: PMID:17954916
    supporting_text: >-
      CUB recognizes both the full-length Cbl-saturated IF complex and the Cbl-saturated
      cleaved IF complex but not the isolated
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:14695536
  title: A genetic polymorphism in the coding region of the gastric intrinsic factor
    gene (GIF) is associated with congenital intrinsic factor deficiency.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Reports the GIF Q5R (mature Q23R) coding polymorphism associated with
      congenital IF deficiency and shows recombinant IF is secreted with native-like
      properties; supports secreted localization and cobalamin binding of the protein.
- id: PMID:15738392
  title: Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic
    factor gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes that biallelic GIF (CBLIF) mutations cause hereditary
      intrinsic factor deficiency (juvenile megaloblastic anemia from B12 malabsorption);
      strong genetic support for CBLIF's role in intestinal cobalamin transport.
- id: PMID:17954916
  title: 'Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A
    resolution.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Crystal structure of human IF-cobalamin; establishes cobalamin
      binding at the two-domain interface and discusses CUBN receptor recognition of the
      Cbl-saturated complex.
- id: PMID:20237569
  title: Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor
    complexes.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (abstract-only in cache). Crystal structure of the IF-Cbl complex bound
      to cubilin CUB(5-8); source of the CUBN IPI and defines cubam receptor recognition.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      PubMed-verified. HuRI high-throughput binary (Y2H) interactome; the CBLIF hits
      (FFAR2, SLC13A4, SLC22A23, SLC7A1, SLC7A14, TMEM237) are unvalidated screen
      interactions with no established biological role for a secreted Cbl-binding protein.
- id: PMID:8886952
  title: Human gastric intrinsic factor expression is not restricted to parietal cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Immuno-localization of intrinsic factor in human gastric mucosa;
      supports parietal-cell production and apical/endocytic membrane localization; source
      of the endosome/microvillus/apical plasma membrane IDA localizations.
- id: file:human/CBLIF/CBLIF-uniprot.txt
  title: UniProtKB entry P27352 (IF_HUMAN), Cobalamin binding intrinsic factor
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt curated record; source of the FUNCTION (secreted cobalamin absorption via
      CUBN), SUBUNIT (interacts with CUBN via CUB domains), secreted subcellular location,
      gastric-mucosa tissue specificity, and IFD disease association.
- id: Reactome:R-HSA-3000103
  title: CUBN:AMN binds CBLIF:RCbl
  findings: []
- id: Reactome:R-HSA-3000120
  title: CBLIF binds RCbl
  findings: []
- id: Reactome:R-HSA-3000137
  title: CUBN:AMN-mediated CBLIF:RCbl uptake and delivery to lysosome
  findings: []
- id: Reactome:R-HSA-3000243
  title: Unknown lysosomal protease degrades CBLIF:RCbl to release Cbl
  findings: []
- id: Reactome:R-HSA-3296462
  title: Defective CUBN does not transport GIF:Cbl
  findings: []
- id: Reactome:R-HSA-3296477
  title: Defective AMN does not transport GIF:Cbl
  findings: []
- id: Reactome:R-HSA-3315455
  title: Defective CBLIF does not bind Cbl
  findings: []
- id: Reactome:R-HSA-9758881
  title: Uptake of dietary cobalamins into enterocytes
  findings: []