id: O60494
gene_symbol: CUBN
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Cubilin is a very large (~3623 aa) peripheral apical-membrane glycoprotein
  built from an N-terminal coiled-coil region, eight EGF-like domains and a cluster
  of 27 CUB domains. It has no transmembrane segment and is tethered to the apical
  plasma membrane through the transmembrane protein amnionless (AMN), with which it
  assembles into the cubam endocytic receptor (one CUBN trimer plus one AMN chain).
  Functioning as a non-enzymatic multiligand cargo receptor, cubilin binds the intrinsic
  factor-cobalamin (IF-B12) complex through its CUB5-8 domains in a calcium-dependent
  manner and, together with AMN and megalin (LRP2), mediates receptor-mediated endocytosis
  of ligands. In the ileum this drives intestinal absorption of dietary vitamin B12,
  while in the renal proximal tubule cubam reabsorbs abundant filtered proteins such
  as albumin, transferrin, vitamin-D-binding protein (GC), apolipoprotein A-I/HDL and
  hemoglobin. Ligands are delivered to endosomes and lysosomes for processing. Loss-of-function
  mutations in CUBN cause Imerslund-Grasbeck syndrome 1 (megaloblastic anemia 1), characterized
  by selective intestinal B12 malabsorption with proteinuria, and C-terminal variants
  are associated with chronic benign proteinuria.
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing cubilin at the plasma membrane.
      Consistent with cubilin acting as a cubam-anchored receptor at the apical cell
      surface. The more specific apical plasma membrane term is preferred as the core
      location, but plasma membrane is correct as a broader term.
    action: ACCEPT
    reason: Cubilin is a peripheral apical-membrane protein and its active site (ligand
      capture and endocytosis) is at the cell surface. Supported by experimental localization.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: anchored to the apical membrane via interaction with the type-1
        transmembrane protein amnionless (AMN)
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation for calcium ion binding, based on
      EGF-like calcium-binding and CUB domains. Cubilin has multiple Ca2+-binding sites
      in its CUB and EGF-like domains, and calcium is required both for structural
      integrity and for ligand binding.
    action: ACCEPT
    reason: Well supported. The crystal structure of the CUB5-8/IF-Cbl complex resolved
      four calcium ions coordinated by CUB domains, and ligand binding is calcium-dependent.
      This is an enabling activity rather than the core receptor function.
    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
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCell electronic annotation to lysosomal membrane. Cubilin traffics
      with its ligands through the endocytic apparatus and can be detected in the lysosomal
      compartment during ligand degradation, but this is a downstream trafficking location
      rather than the core functional site.
    action: KEEP_AS_NON_CORE
    reason: Endocytosed ligands are delivered to lysosomes and cubilin can localize
      to the lysosomal membrane transiently, but the functionally defining location
      is the apical plasma membrane where ligand capture occurs.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Lysosome membrane
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCell electronic annotation to endosome. Cubilin/cubam and its
      cargo are internalized into endosomes as part of the receptor-mediated endocytosis
      pathway. Directly supported experimentally.
    action: ACCEPT
    reason: Endosomal localization is part of the endocytic itinerary of the cubam receptor
      and is experimentally documented (see the IDA/EXP endosome annotations for this
      gene).
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin trafficked to the cell surface and endosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCell electronic annotation to plasma membrane. Correct; cubilin
      is displayed at the cell surface as part of the AMN-anchored cubam complex.
    action: ACCEPT
    reason: Consistent with experimental and phylogenetic annotations placing cubilin
      at the (apical) plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCell electronic annotation to the generic membrane term. True
      but uninformative given the more specific apical/plasma membrane annotations.
    action: ACCEPT
    reason: Correct as a high-level parent of the more specific (apical) plasma membrane
      localization. Retained but subsumed by more specific terms.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined-methods (IEA) annotation to apical plasma membrane. This is the
      core functional location of cubilin, which is displayed on the apical/brush-border
      surface of enterocytes and proximal tubule cells.
    action: ACCEPT
    reason: Apical plasma membrane is the defining site of cubilin function, well supported
      experimentally (IDA) and by orthology (ISS) as well as this IEA.
    supported_by:
    - reference_id: PMID:29402915
      supporting_text: cubilin is secreted at the apical surface in a glycosylation-dependent
        process
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA (IEA) annotation to endocytic vesicle. Consistent with cubilin's role
      in receptor-mediated endocytosis and its experimentally documented endocytic-vesicle
      localization.
    action: ACCEPT
    reason: Cubilin/cubam and cargo are internalized into endocytic vesicles; supported
      by the experimental IDA endocytic vesicle annotation for this gene.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin and AMN colocalize in the endocytic apparatus of polarized
        epithelial cells
- term:
    id: GO:0031253
    label: cell projection membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA (IEA) annotation to cell projection membrane. Cubilin localizes to
      the microvillus/brush-border membrane, which is a cell-projection membrane, so
      this is a correct broader term.
    action: ACCEPT
    reason: Consistent with the microvillus/brush-border membrane annotations; cell
      projection membrane is an accurate parent term for the microvilli of the brush
      border.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: cubam location the enterocyte brush-border membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20237569
  qualifier: enables
  review:
    summary: Bare protein binding IPI capturing the physical interaction with intrinsic
      factor (CBLIF, P27352), which is the ligand recognized by cubilin's CUB5-8 domains.
      The term itself is uninformative; the biologically meaningful function is cargo/receptor
      activity toward the IF-cobalamin complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Per curation guidelines the generic protein binding term should be avoided.
      The interaction it records (with CBLIF) is better captured by the cargo receptor
      activity MF and the cubam complex; per policy the IPI is not removed but flagged
      as over-annotated.'
    supported_by:
    - reference_id: PMID:20237569
      supporting_text: the crystal structure of the complex between IF-Cbl and the cubilin
        IF-Cbl-binding-region (CUB(5-8))
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30523278
  qualifier: enables
  review:
    summary: Bare protein binding IPI capturing the physical interaction with amnionless
      (AMN, Q9BXJ7), the partner that anchors cubilin to the apical membrane in the
      cubam complex. The generic term is uninformative; the interaction is better captured
      by cubam complex membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative. The AMN interaction is more precisely
      represented by the cubam receptor complex membership; per policy the IPI is retained
      but flagged as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: combine into an intertwined β-helical structure that docks on
        to a corresponding β-helix domain in AMN
- 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 for cobalamin transport ("Uptake of dietary cobalamins
      into enterocytes"). This is a core biological process for cubilin, which as part
      of cubam mediates intestinal uptake of IF-bound B12.
    action: ACCEPT
    reason: Cobalamin transport (intestinal uptake of IF-B12) is the best-characterized
      physiological role of cubilin and is well supported by multiple lines of evidence.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: the cells exhibited IF-cobalamin endocytosis and lysosomal degradation
        of IF
- term:
    id: GO:0042359
    label: vitamin D metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196791
  qualifier: involved_in
  review:
    summary: Reactome TAS annotation for vitamin D metabolic process. Cubilin, with
      megalin, reabsorbs vitamin-D-binding protein (GC) carrying 25(OH)D from the glomerular
      filtrate, contributing to vitamin D handling. This is a physiologically relevant
      but non-core role.
    action: KEEP_AS_NON_CORE
    reason: Cubilin binds GC:25(OH)D and participates in renal handling of vitamin D
      via reabsorption, but this is one of many reabsorbed ligands and is downstream
      of its core cargo-receptor/endocytosis function.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Acts together with LRP2 to mediate endocytosis of high-density
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-350186
  qualifier: enables
  review:
    summary: Reactome TAS annotation for cargo receptor activity ("CUBN binds GC:25(OH)D").
      This is the core molecular function of cubilin - a non-enzymatic multiligand cargo/endocytic
      receptor.
    action: ACCEPT
    reason: Cargo receptor activity is the defining molecular function of cubilin, supported
      by extensive experimental data (binding of IF-cobalamin and multiple other ligands
      for endocytosis).
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Endocytic receptor which plays a role in lipoprotein, vitamin
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: involved_in
  review:
    summary: ComplexPortal IDA annotation for cobalamin transport based on the demonstration
      that the cubilin/AMN (cubam) complex mediates IF-cobalamin endocytosis and delivery
      to lysosomes. Core biological process.
    action: ACCEPT
    reason: Direct experimental evidence that cubam confers IF-cobalamin endocytosis;
      this is cubilin's canonical transport role.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: the cells exhibited IF-cobalamin endocytosis and lysosomal degradation
        of IF
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: ComplexPortal IDA annotation to the generic membrane term. Correct but
      subsumed by the more specific apical plasma / microvillus membrane annotations.
    action: ACCEPT
    reason: Correct high-level location; cubilin is a peripheral membrane protein at
      the cell surface. Retained as a broad parent of more specific terms.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin trafficked to the cell surface and endosomes
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: ComplexPortal NAS annotation to apical plasma membrane. Cubilin (via cubam)
      is displayed on the apical surface of polarized epithelial cells; this is its
      core functional location.
    action: ACCEPT
    reason: Apical plasma membrane is the defining functional site of cubilin, supported
      by experimental localization in intestinal and renal epithelia.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin trafficked to the cell surface and endosomes
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: ComplexPortal IDA annotation to endocytic vesicle, based on colocalization
      of cubilin and AMN in the endocytic apparatus and internalization of IF-cobalamin.
    action: ACCEPT
    reason: Direct experimental support for endocytic-vesicle localization as part of
      the receptor-mediated endocytosis pathway.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin and AMN colocalize in the endocytic apparatus of polarized
        epithelial cells
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: Duplicate IDA annotation to endocytic vesicle (UniProt-assigned, same
      supporting study). Reflects internalization of cubilin/cubam and cargo into endocytic
      vesicles during receptor-mediated endocytosis.
    action: ACCEPT
    reason: Consistent with the ComplexPortal endocytic-vesicle annotation; a genuine
      duplicate from a different assigning source.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin and AMN colocalize in the endocytic apparatus of polarized
        epithelial cells
- term:
    id: GO:0043235
    label: signaling receptor complex
  evidence_type: IPI
  original_reference_id: PMID:30523278
  qualifier: part_of
  review:
    summary: ComplexPortal IPI annotation placing cubilin in a receptor complex, reflecting
      the cubam complex (one CUBN trimer plus one AMN chain). Cubam is an endocytic/cargo
      receptor complex rather than a signaling receptor complex, so the term label is
      somewhat imprecise, but complex membership is accurate.
    action: ACCEPT
    reason: Cubilin is genuinely part of the cubam receptor complex with AMN. The "signaling"
      qualifier of this term is a minor misnomer (cubilin is an endocytic, not signaling,
      receptor), but the assertion of receptor-complex membership is experimentally
      correct.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: combine into an intertwined β-helical structure that docks on
        to a corresponding β-helix domain in AMN
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: EXP
  original_reference_id: PMID:14576052
  qualifier: enables
  review:
    summary: Experimental annotation for cargo receptor activity from the study showing
      that cubilin, complexed with AMN as cubam, confers IF-cobalamin endocytosis. Core
      molecular function.
    action: ACCEPT
    reason: Direct experimental demonstration of cubilin as the ligand-binding subunit
      of an endocytic cargo receptor.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: AMN binds to the amino-terminal third of cubilin and directs
        subcellular localization and endocytosis of cubilin with its ligand
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: EXP
  original_reference_id: PMID:20237569
  qualifier: enables
  review:
    summary: Experimental annotation for cargo receptor activity based on the crystal
      structure showing how cubilin CUB5-8 recognizes IF-cobalamin. Directly establishes
      cubilin's ligand-recognition (cargo receptor) function.
    action: ACCEPT
    reason: The structure defines the molecular basis of cubilin's cargo-receptor recognition
      of the IF-Cbl ligand, supporting the core MF.
    supported_by:
    - reference_id: PMID:20237569
      supporting_text: the crystal structure of the complex between IF-Cbl and the cubilin
        IF-Cbl-binding-region (CUB(5-8))
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: EXP
  original_reference_id: PMID:30523278
  qualifier: enables
  review:
    summary: Experimental annotation for cargo receptor activity based on the structural
      assembly of cubam, the receptor for intestinal B12 uptake and kidney protein reabsorption.
      Core molecular function.
    action: ACCEPT
    reason: Establishes cubilin as the multivalent ligand-binding component of the cubam
      endocytic receptor.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: essential for intestinal vitamin B12 (B12) uptake and for protein
        (e.g. albumin) reabsorption from the kidney filtrate
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS annotation to lysosomal membrane by transfer from rodent ortholog (O70244).
      Reflects trafficking of cubilin/cargo to the lysosome during ligand degradation;
      a non-core, downstream location.
    action: KEEP_AS_NON_CORE
    reason: Consistent with delivery of endocytosed ligands to lysosomes, but the defining
      functional location is the apical plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Lysosome membrane
- term:
    id: GO:0005768
    label: endosome
  evidence_type: EXP
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: Experimental annotation to endosome, based on the demonstration that cubilin
      trafficks to the cell surface and endosomes when co-expressed with AMN. Part of
      the endocytic pathway.
    action: ACCEPT
    reason: Directly supported experimental endosomal localization consistent with cubilin's
      receptor-mediated endocytosis role.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin trafficked to the cell surface and endosomes
- term:
    id: GO:0005768
    label: endosome
  evidence_type: EXP
  original_reference_id: PMID:29402915
  qualifier: located_in
  review:
    summary: Experimental annotation to endosome from the study of AMN-mediated cubilin
      surface targeting, which documented internalization of cubilin from the apical
      surface into vesicles. Endocytic-pathway localization.
    action: ACCEPT
    reason: Cubilin is internalized from the apical surface into the endocytic/endosomal
      compartment; experimentally supported.
    supported_by:
    - reference_id: PMID:29402915
      supporting_text: mini-cubilin was internalised from the apical surface
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: Experimental annotation to plasma membrane, based on the demonstration
      that cubilin trafficks to the cell surface only when co-expressed with AMN. Core
      surface location.
    action: ACCEPT
    reason: Direct experimental evidence for plasma-membrane (cell-surface) localization
      of cubilin as part of the cubam complex.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin trafficked to the cell surface and endosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:29402915
  qualifier: located_in
  review:
    summary: Experimental annotation to plasma membrane from the AMN-dependent surface-targeting
      study, which showed AMN-dependent cubilin plasma-membrane expression in renal
      and intestinal cells.
    action: ACCEPT
    reason: Direct experimental support for AMN-dependent plasma-membrane localization.
    supported_by:
    - reference_id: PMID:29402915
      supporting_text: when cubilin was co-expressed with amnionless, a fraction of
        cubilin expressed at the plasma membrane was detected
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:30523278
  qualifier: located_in
  review:
    summary: Experimental annotation to plasma membrane from the cubam structural-assembly
      study, which established that cubilin is anchored to the apical membrane via AMN.
    action: ACCEPT
    reason: Cubilin is displayed at the (apical) plasma membrane through AMN anchoring;
      experimentally supported.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: anchored to the apical membrane via interaction with the type-1
        transmembrane protein amnionless (AMN)
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS annotation to apical plasma membrane by transfer from rodent ortholog
      (Q9JLB4). Consistent with the core apical localization of cubilin.
    action: ACCEPT
    reason: Apical plasma membrane is the core functional location, well supported experimentally
      and by orthology.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Duplicate ISS annotation to apical plasma membrane, transferred from a second
      rodent ortholog (O70244). Consistent with the core apical localization of cubilin.
    action: ACCEPT
    reason: Genuine duplicate of the apical plasma membrane ISS from a different ortholog;
      apical plasma membrane is the core functional location.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: acts_upstream_of_or_within
  review:
    summary: MGI IDA annotation to cobalamin metabolic process (acts_upstream_of_or_within).
      Cubilin mediates intestinal B12 uptake, which is upstream of cellular cobalamin
      metabolism. The direct role is transport; the metabolic-process framing is broader.
    action: KEEP_AS_NON_CORE
    reason: Cubilin's direct action is cobalamin transport/uptake, which is upstream
      of cobalamin metabolism. The metabolic-process term is a valid broader/upstream
      description but not the most precise statement of cubilin's function.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: intestinal cobalamin (vitamin B(12)) malabsorption
- term:
    id: GO:0031528
    label: microvillus membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: MGI IDA annotation to microvillus membrane. Cubilin localizes to the brush-border
      microvilli of enterocytes and proximal tubule cells; a specific and accurate apical
      location.
    action: ACCEPT
    reason: Microvillus (brush border) membrane is a precise and correct description
      of cubilin's apical localization in absorptive epithelia.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: cubam location the enterocyte brush-border membrane
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: enables
  review:
    summary: MGI IDA annotation for cargo receptor activity, from the demonstration that
      cubam confers IF-cobalamin endocytosis. Core molecular function.
    action: ACCEPT
    reason: Direct experimental evidence for cubilin's cargo/endocytic receptor function.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: AMN binds to the amino-terminal third of cubilin and directs
        subcellular localization and endocytosis of cubilin with its ligand
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: enables
  review:
    summary: Duplicate MGI IDA annotation for cargo receptor activity from the same
      supporting study (a separate MGI annotation record). Core molecular function of
      cubilin as the ligand-binding subunit of the cubam endocytic receptor.
    action: ACCEPT
    reason: Genuine duplicate of the MGI cargo receptor activity IDA; direct experimental
      support for cubilin's cargo/endocytic receptor function.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: AMN binds to the amino-terminal third of cubilin and directs
        subcellular localization and endocytosis of cubilin with its ligand
- term:
    id: GO:0031528
    label: microvillus membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: is_active_in
  review:
    summary: MGI IDA annotation (is_active_in) to microvillus membrane, indicating that
      cubilin acts at the brush-border microvillus membrane. Consistent with the core
      apical site of ligand capture.
    action: ACCEPT
    reason: The microvillus (brush border) membrane is where cubilin performs its ligand-capture
      function; correct and precise active-site localization.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: cubam location the enterocyte brush-border membrane
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: involved_in
  review:
    summary: MGI IDA annotation (involved_in) to cobalamin metabolic process. As with
      the acts_upstream_of_or_within duplicate, cubilin's direct role is B12 transport/uptake,
      which is part of overall cobalamin metabolism.
    action: KEEP_AS_NON_CORE
    reason: Cubilin participates in cobalamin metabolism by mediating uptake; the more
      precise statement is cobalamin transport (retained as core). Kept as non-core broader
      process.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: intestinal cobalamin (vitamin B(12)) malabsorption
- term:
    id: GO:0043235
    label: signaling receptor complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: ISS annotation placing cubilin in a receptor complex, by transfer from rodent
      ortholog (O70244). Reflects the cubam complex. As with the IPI duplicate, "signaling"
      is a minor misnomer for what is an endocytic/cargo receptor complex.
    action: ACCEPT
    reason: Cubilin is genuinely part of the cubam receptor complex with AMN; complex
      membership is accurate even though the "signaling" qualifier is imprecise.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Component of the cubam complex
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: TAS
  original_reference_id: PMID:9478979
  qualifier: enables
  review:
    summary: GO_Central TAS annotation for cargo receptor activity, from the original
      molecular characterization of cubilin as the 460-kDa peripheral membrane receptor
      that facilitates uptake of IF-B12. Core molecular function.
    action: ACCEPT
    reason: The founding characterization of cubilin identified it as the endocytic receptor
      facilitating IF-B12 uptake, the basis for its cargo-receptor MF.
    supported_by:
    - reference_id: PMID:9478979
      supporting_text: functions as the receptor facilitating uptake of intrinsic factor-vitamin
        B12 complexes in the intestine and kidney
- term:
    id: GO:0031526
    label: brush border membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS annotation to brush border membrane by transfer from rodent ortholog
      (O70244). Cubilin is a brush-border receptor of absorptive epithelia; specific
      and accurate apical location.
    action: ACCEPT
    reason: Brush border membrane is a precise, correct description of cubilin's apical
      localization; supported experimentally and by orthology.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: cubam location the enterocyte brush-border membrane
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput proteomics (HDA) detection of cubilin in prostatic-secretion/urinary
      exosomes. Reflects shedding of the apical brush-border protein into extracellular
      vesicles rather than a functional site.
    action: KEEP_AS_NON_CORE
    reason: Detection in exosomes is a byproduct of cubilin's abundant apical membrane
      localization and its shedding into urine; not a functional localization but a
      valid observation.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: exosome preparations were characterized by a shotgun proteomics
        procedure
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: IDA
  original_reference_id: PMID:21082674
  qualifier: located_in
  review:
    summary: IDA detection of cubilin in low-abundance urinary-exosome proteomics. As
      above, reflects shedding of the apical membrane protein into urinary exosomes
      rather than a functional site.
    action: KEEP_AS_NON_CORE
    reason: Consistent with cubilin's presence in urinary exosomes shed from renal epithelia;
      a non-functional localization observation.
    supported_by:
    - reference_id: PMID:21082674
      supporting_text: relatively low-abundant proteins in urinary exosomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14576052
  qualifier: enables
  review:
    summary: Bare protein binding IPI capturing the physical interaction with amnionless
      (AMN, Q9BXJ7) demonstrated during the identification of the cubam complex. The
      generic term is uninformative; the interaction is better captured by cubam complex
      membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative per curation guidelines. The AMN
      interaction is more precisely represented by cubam complex membership; the IPI
      is retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomics (HDA) detection of cubilin in the human urinary-exosome
      proteome. Reflects shedding into urinary exosomes rather than a functional site.
    action: KEEP_AS_NON_CORE
    reason: Consistent with cubilin's abundance at the apical surface of renal epithelia
      and its shedding into urinary exosomes; a non-functional localization observation.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: profile the proteome of human urinary exosomes
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: UniProt IDA annotation to apical plasma membrane. Core functional location
      of cubilin as displayed on polarized epithelial apical surfaces.
    action: ACCEPT
    reason: Apical plasma membrane is the defining functional site of cubilin; experimentally
      supported.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: cubilin trafficked to the cell surface and endosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3296462
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (from a defective-CUBN transport
      reaction). Correct high-level location subsumed by the apical plasma membrane
      annotations.
    action: ACCEPT
    reason: Correct as a broad location for the cell-surface receptor; retained as parent
      of apical plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-209760
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol, arising from Reactome pathway modeling
      of endocytic translocation reactions. Cubilin is a peripheral, extracellular-facing
      membrane protein without a cytoplasmic domain, so a cytosolic localization is
      biologically implausible and likely an artifact of pathway-reaction compartment
      assignment.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cubilin lacks a transmembrane and cytoplasmic domain and faces the extracellular/luminal
      space; it is not a cytosolic protein. The cytosol assignment reflects Reactome
      reaction compartmentalization rather than genuine cytosolic function.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Lacks a transmembrane domain and depends on
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-350168
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol (from the LRP2-mediated uptake reaction).
      As above, cubilin is an extracellular-facing peripheral membrane protein, so cytosolic
      localization is an artifact of Reactome reaction compartments.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cubilin is not a cytosolic protein; this reflects Reactome pathway modeling
      rather than genuine localization.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Lacks a transmembrane domain and depends on
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-209760
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to lysosomal lumen, from the pathway modeling of
      endocytic delivery of the CUBN:GC:25(OH)D complex to the lysosome. Reflects trafficking
      of endocytosed cargo to lysosomes; a downstream, non-core location.
    action: KEEP_AS_NON_CORE
    reason: Endocytosed ligands and cubilin can be delivered to the lysosome for degradation;
      a valid downstream location but not the core functional site.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: lysosomal degradation of IF
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-350158
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to lysosomal lumen (LGMN-mediated release of CUBN
      and 25(OH)D). Downstream lysosomal delivery of endocytosed cargo; non-core location.
    action: KEEP_AS_NON_CORE
    reason: Consistent with delivery of cubilin-bound cargo to the lysosome; downstream,
      non-core.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: lysosomal degradation of IF
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264834
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (endocytosis/degradation of
      apoA-I reaction). Correct broad cell-surface location.
    action: ACCEPT
    reason: Cubilin at the plasma membrane captures apoA-I/HDL for endocytosis; correct
      broad location subsumed by apical plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Acts together with LRP2 to mediate endocytosis of high-density
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264848
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (apoA-I binds CUBN:AMN reaction).
      Correct broad cell-surface location.
    action: ACCEPT
    reason: Consistent with cubilin's cell-surface (apical) localization where it binds
      apoA-I; retained as broad parent term.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000103
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (CUBN:AMN binds CBLIF:RCbl reaction).
      Correct broad cell-surface location where IF-cobalamin is captured.
    action: ACCEPT
    reason: Correct broad location; cubam binds IF-cobalamin at the (apical) plasma
      membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000137
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (CUBN:AMN-mediated CBLIF:RCbl
      uptake reaction). Correct broad cell-surface location.
    action: ACCEPT
    reason: Consistent with cubam-mediated IF-cobalamin uptake at the cell surface;
      retained as broad parent of apical plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3296477
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (defective-AMN transport reaction).
      Correct broad cell-surface location.
    action: ACCEPT
    reason: Correct broad location for the cubam receptor at the cell surface.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-350168
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (LRP2-mediated uptake of extracellular
      CUBN:GC:25(OH)D reaction). Correct broad cell-surface location.
    action: ACCEPT
    reason: Consistent with cubilin's cell-surface localization; retained as broad parent
      of apical plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-350186
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to plasma membrane (CUBN binds GC:25(OH)D reaction).
      Correct broad cell-surface location.
    action: ACCEPT
    reason: Correct broad location where cubilin binds vitamin-D-binding protein for
      reabsorption; retained as parent of apical plasma membrane.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0001894
    label: tissue homeostasis
  evidence_type: NAS
  original_reference_id: PMID:11994745
  qualifier: involved_in
  review:
    summary: NAS annotation to tissue homeostasis from a review of megalin/cubilin as
      multifunctional endocytic receptors. This is a very general process term; cubilin's
      contributions (protein/vitamin reabsorption) are better captured by specific transport/endocytosis
      terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tissue homeostasis is too vague to be informative for cubilin. Its physiological
      roles are more precisely described by cobalamin transport, receptor-mediated endocytosis
      and protein reabsorption.
    supported_by:
    - reference_id: PMID:11994745
      supporting_text: Megalin and cubilin are two structurally different endocytic
        receptors that interact to serve such functions
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: NAS
  original_reference_id: PMID:11994745
  qualifier: involved_in
  review:
    summary: NAS annotation to receptor-mediated endocytosis from the megalin/cubilin
      review. This is the core mechanistic process by which cubilin/cubam internalizes
      IF-cobalamin and reabsorbed proteins.
    action: ACCEPT
    reason: Receptor-mediated endocytosis is the defining biological process of cubilin,
      well supported across the literature.
    supported_by:
    - reference_id: PMID:11994745
      supporting_text: Megalin and cubilin are two structurally different endocytic
        receptors that interact to serve such functions
- term:
    id: GO:0031232
    label: extrinsic component of external side of plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:11994745
  qualifier: located_in
  review:
    summary: NAS annotation describing cubilin as an extrinsic (peripheral) component
      of the external side of the plasma membrane. This is an accurate and informative
      topology statement - cubilin lacks a transmembrane domain and is peripheral, facing
      the extracellular/luminal space.
    action: ACCEPT
    reason: Accurate description of cubilin's membrane topology; it is a peripheral membrane
      protein displayed on the extracellular side of the apical membrane through AMN.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Lacks a transmembrane domain and depends on
- term:
    id: GO:0031526
    label: brush border membrane
  evidence_type: NAS
  original_reference_id: PMID:11994745
  qualifier: located_in
  review:
    summary: NAS annotation to brush border membrane. Cubilin is a brush-border receptor
      of absorptive epithelia; a specific and correct apical location.
    action: ACCEPT
    reason: Brush border membrane accurately describes cubilin's apical localization
      in intestinal and renal epithelia.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: cubam location the enterocyte brush-border membrane
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:10552972
  qualifier: enables
  review:
    summary: UniProt IDA annotation for protein homodimerization activity, cited to
      the canine genetics study of an accessory activity required for cubilin brush-border
      expression. The cached abstract addresses genetic linkage (an accessory protein
      required for cubilin surface expression) and does not describe a homodimerization
      assay; the full text is not available to verify the supporting evidence. Structurally,
      cubilin is now known to trimerize via its N-terminal beta-helix rather than simply
      homodimerize.
    action: UNDECIDED
    reason: The self-association MF is plausible (cubilin oligomerizes - it forms trimers
      and cubam can dimerize) but "homodimerization" is imprecise, and I cannot verify
      the experimental basis from the cached abstract of the cited reference. Per policy,
      UNDECIDED rather than REMOVE for an experimental annotation whose full text is
      unavailable.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: potential of dimerization into an even larger complex
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: PMID:10080186
  qualifier: involved_in
  review:
    summary: PINC TAS annotation for cobalamin transport, citing the paper identifying
      CUBN mutations as the cause of hereditary megaloblastic anemia 1 via selective
      intestinal B12 malabsorption. Core biological process.
    action: ACCEPT
    reason: Genetic evidence that CUBN loss causes selective intestinal B12 malabsorption
      directly supports cubilin's role in cobalamin transport.
    supported_by:
    - reference_id: PMID:10080186
      supporting_text: MGA1 is characterized by selective intestinal vitamin B12 (B12,
        cobalamin) malabsorption
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:9478979
  qualifier: located_in
  review:
    summary: PINC TAS annotation to the generic membrane term, from the original characterization
      of cubilin as a peripheral membrane receptor. Correct but high-level.
    action: ACCEPT
    reason: Correct as a broad location; cubilin is a peripheral membrane protein. Subsumed
      by more specific apical/brush-border membrane terms.
    supported_by:
    - reference_id: PMID:9478979
      supporting_text: a megalin-binding peripheral membrane protein
- term:
    id: GO:0038023
    label: signaling receptor activity
  evidence_type: TAS
  original_reference_id: PMID:10080186
  qualifier: enables
  review:
    summary: Old PINC TAS annotation to signaling receptor activity. This is a misclassification -
      cubilin is an endocytic/cargo receptor, not a signal-transducing (signaling) receptor.
      It has no signaling domain and no described role in signal transduction; its function
      is ligand capture for endocytosis.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cubilin is a non-enzymatic endocytic cargo receptor (cargo receptor activity,
      GO:0038024), not a signaling receptor. The signaling receptor activity term mischaracterizes
      its molecular function; the correct MF is already annotated. Per policy for a TAS
      mapping that is biologically wrong in kind, this is flagged as over-annotated.
    supported_by:
    - reference_id: file:human/CUBN/CUBN-uniprot.txt
      supporting_text: Endocytic receptor which plays a role in lipoprotein, vitamin
core_functions:
- description: Non-enzymatic multiligand cargo/endocytic receptor that binds the intrinsic
    factor-cobalamin (IF-B12) complex via its CUB5-8 domains and, together with AMN
    (cubam) and megalin, mediates receptor-mediated endocytosis of B12 and reabsorbed
    proteins.
  molecular_function:
    id: GO:0038024
    label: cargo receptor activity
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  in_complex:
    id: GO:0043235
    label: receptor complex
  supported_by:
  - reference_id: PMID:14576052
    supporting_text: AMN binds to the amino-terminal third of cubilin and directs subcellular
      localization and endocytosis of cubilin with its ligand
  - 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
- description: As the ligand-binding subunit of the cubam receptor at the apical/brush-border
    membrane, cubilin captures diverse filtered and luminal ligands for receptor-mediated
    endocytosis, driving intestinal B12 uptake and renal proximal-tubule reabsorption
    of proteins.
  molecular_function:
    id: GO:0038024
    label: cargo receptor activity
  directly_involved_in:
  - id: GO:0006898
    label: receptor-mediated endocytosis
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  - id: GO:0031526
    label: brush border membrane
  supported_by:
  - reference_id: PMID:9478979
    supporting_text: functions as the receptor facilitating uptake of intrinsic factor-vitamin
      B12 complexes in the intestine and kidney
  - reference_id: PMID:30523278
    supporting_text: it is responsible for reabsorption of abundant proteins in the
      renal ultrafiltrate
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10080186
  title: Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin,
    cause hereditary megaloblastic anaemia 1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes that CUBN loss-of-function causes selective
      intestinal B12 malabsorption (MGA1/IGS1), supporting the cobalamin transport role.
- id: PMID:10552972
  title: Genetic evidence of an accessory activity required specifically for cubilin
    brush-border expression and intrinsic factor-cobalamin absorption.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Canine genetics paper showing an accessory (AMN-like)
      activity is required for cubilin brush-border expression; cited for a homodimerization
      IDA whose experimental basis is not evident in the abstract (full text unavailable).
- id: PMID:11994745
  title: 'Megalin and cubilin: multifunctional endocytic receptors.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified review establishing cubilin (with megalin) as a multifunctional
      endocytic receptor; source of the receptor-mediated endocytosis annotation.
- id: PMID:14576052
  title: The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel
    complex of cubilin and amnionless.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Defines the cubam (cubilin/AMN) complex and shows
      AMN directs cubilin surface localization and IF-cobalamin endocytosis; anchors
      the cargo-receptor MF and cobalamin transport BP.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified urinary-exosome proteomics; supports only the incidental
      extracellular exosome localization, not a functional role.
- 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 crystal structure of CUB5-8/IF-Cbl; defines the calcium-dependent
      dual-point recognition mechanism underlying the cargo-receptor and calcium-binding
      functions.
- id: PMID:21082674
  title: Comprehensive analysis of low-abundance proteins in human urinary exosomes
    using peptide ligand library technology, peptide OFFGEL fractionation and nanoHPLC-chip-MS/MS.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified urinary-exosome proteomics; supports only incidental
      exosome localization.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified exosome proteomics; supports only incidental exosome
      localization.
- id: PMID:29402915
  title: Amnionless-mediated glycosylation is crucial for cell surface targeting of
    cubilin in renal and intestinal cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified full text. Shows AMN-dependent glycosylation and plasma-membrane/apical
      targeting of cubilin and ER retention of mutants; supports localization annotations.
- id: PMID:30523278
  title: Structural assembly of the megadalton-sized receptor for intestinal vitamin
    B(12) uptake and kidney protein reabsorption.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified full text. Cubam structure - three cubilin chains
      dock onto AMN; establishes apical anchoring, trimer/dimer architecture and roles
      in B12 uptake and renal reabsorption.
- id: PMID:9478979
  title: The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies
    is a megalin-binding peripheral membrane protein with homology to developmental
    proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Original molecular characterization naming cubilin;
      identifies it as a peripheral (non-transmembrane) EGF/CUB-domain endocytic receptor
      for IF-B12.
- id: Reactome:R-HSA-196791
  title: Vitamin D (calciferol) metabolism
  findings: []
- id: Reactome:R-HSA-209760
  title: Endocytic translocation of CUBN:GC:25(OH)D to lysosomal lumen
  findings: []
- id: Reactome:R-HSA-264834
  title: Endocytosis and degradation of apoA-I
  findings: []
- id: Reactome:R-HSA-264848
  title: apoA-I binds to CUBN:AMN
  findings: []
- id: Reactome:R-HSA-3000103
  title: CUBN:AMN binds CBLIF:RCbl
  findings: []
- id: Reactome:R-HSA-3000137
  title: CUBN:AMN-mediated CBLIF:RCbl uptake and delivery to lysosome
  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-350158
  title: LGMN hydrolyzes GC, releasing CUBN and 25(OH)D
  findings: []
- id: Reactome:R-HSA-350168
  title: LRP2-mediated uptake of extracellular CUBN:GC:25(OH)D
  findings: []
- id: Reactome:R-HSA-350186
  title: CUBN binds GC:25(OH)D
  findings: []
- id: Reactome:R-HSA-9758881
  title: Uptake of dietary cobalamins into enterocytes
  findings: []
- id: file:human/CUBN/CUBN-uniprot.txt
  title: UniProtKB entry O60494 (CUBN_HUMAN), Cubilin
  findings: []