id: Q9BXJ7
gene_symbol: AMN
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AMN (amnionless) is a single-pass type I transmembrane glycoprotein that partners
  cubilin (CUBN) to form the cubam endocytic receptor. Cubilin carries the ligand-binding
  CUB domains but lacks a transmembrane segment and cytoplasmic endocytosis signals; AMN
  supplies both, acting as the membrane-anchoring/endocytic co-receptor subunit. AMN is
  required for the correct N-glycosylation, apical cell-surface targeting and clathrin-mediated
  internalization of cubilin together with its bound ligands. It is non-enzymatic: its
  extracellular region docks the amino-terminal region of cubilin (a single AMN chain binding
  three cubilin subunits), its transmembrane helix anchors the complex, and its cytoplasmic tail
  contains two redundant FXNPXF internalization motifs that engage the clathrin adaptors ARH
  (LDLRAP1) and Dab2. Cubam operates at the apical/microvillus (brush border) membrane of ileal
  enterocytes, where it mediates uptake of dietary vitamin B12 (cobalamin) complexed with intrinsic
  factor, and of renal proximal tubule cells, where it reabsorbs filtered low-molecular-weight
  proteins (e.g. albumin, transferrin, apolipoprotein A-I, vitamin D-binding protein). Loss-of-function
  variants in AMN cause Imerslund-Grasbeck syndrome 2 (megaloblastic anemia 1 with proteinuria),
  the same selective B12-malabsorption disorder produced by CUBN mutations.
existing_annotations:
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cubam (AMN+cubilin) is active at the apical plasma membrane of ileal enterocytes and
      renal proximal tubule cells; AMN provides the membrane anchor. This is a well-supported
      core localization consistent with experimental data.
    action: ACCEPT
    reason: >-
      IBA localization at the apical plasma membrane is corroborated by direct experimental
      evidence in the same gene (PMID:14576052 apical cell membrane; PMID:29402915 cell-surface
      targeting). This is the physiological site of cubam action.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      AMN is the membrane-anchoring/endocytic subunit of the cubam cargo receptor: it anchors
      the ligand-binding cubilin subunits to the membrane and directs their endocytosis. Cargo
      receptor activity is the correct molecular-function abstraction for this co-receptor role.
    action: ACCEPT
    reason: >-
      Cargo receptor activity is the core molecular function. AMN binds the ligand-binding cubilin
      subunits, anchors them via its transmembrane helix, and internalizes bound cargo (IF-B12,
      filtered proteins) via clathrin-coated pits. Supported by IBA and by direct experimental
      annotation from the same paper.
    supported_by:
    - reference_id: PMID:20088845
      supporting_text: >-
        cubilin contains no transmembrane segment and therefore needs the transmembrane region
        of AMN to be anchored in the plasma membrane
- term:
    id: GO:0043235
    label: signaling receptor complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      AMN is part of a receptor complex (cubam), but cubam is a nutrient/cargo endocytic receptor,
      not a signaling receptor. The "signaling" framing is an over-interpretation; the informative,
      accurate content is captured by cargo receptor activity and receptor-mediated endocytosis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Cubam mediates ligand binding and endocytosis (uptake), not signal transduction. There is no
      evidence AMN participates in a signaling receptor complex; the endocytic-receptor role is the
      correct one. Marking as over-annotated rather than removing an IBA that reflects a generic
      "receptor complex" tree assignment.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: PANTHER:PTN001029969
        source_label: AMN family node
      - source_id: UniProtKB:Q9BXJ7
        source_label: AMN (human)
    supported_by:
    - reference_id: PMID:20088845
      supporting_text: >-
        Cubam is a multi-ligand receptor involved in dietary uptake of intrinsic factor-vitamin
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: >-
        Membrane-bound component of the endocytic receptor formed by
- term:
    id: GO:0097017
    label: renal protein absorption
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      In the renal proximal tubule, cubam reabsorbs filtered low-molecular-weight proteins
      (albumin, transferrin, apoA-I, vitamin D-binding protein). AMN is required for this
      CUBN-mediated renal protein reabsorption; the mild proteinuria in IGS2 reflects its loss.
    action: ACCEPT
    reason: >-
      Well-supported physiological role. IBA plus literature: cubam reabsorbs proteins from the
      glomerular ultrafiltrate, and AMN is required for cubilin's renal protein transport.
    supported_by:
    - reference_id: PMID:20088845
      supporting_text: >-
        cubam is involved in reabsorption of various proteins from the glomerular ultrafiltrate
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      AMN directs clathrin/receptor-mediated endocytosis of the cubam receptor and its ligands via
      two redundant FXNPXF motifs that engage ARH and Dab2. Core biological process.
    action: ACCEPT
    reason: >-
      Directly supported experimentally: the AMN cytoplasmic FXNPXF signals mediate internalization
      of cubam through ARH/Dab2 and clathrin-coated pits. IBA is corroborated by IDA/IMP.
    supported_by:
    - reference_id: PMID:20088845
      supporting_text: >-
        both are able to mediate endocytosis of cubam through interaction with Dab2 and ARH
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      AMN directs the subcellular localization of cubilin: it is required to move cubilin out of
      early biosynthetic compartments to the cell surface and endosomes. Reflects AMN's chaperone/
      trafficking role for its partner.
    action: ACCEPT
    reason: >-
      Supported by experimental data: without AMN, cubilin accumulates in early biosynthetic
      compartments; with AMN, cubilin traffics to the surface and endosomes. AMN thus governs
      intracellular localization of the 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
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cubam is internalized into and cycles through endocytic vesicles; AMN is active there during
      cargo internalization and receptor recycling.
    action: ACCEPT
    reason: >-
      Consistent with the receptor-mediated endocytosis role and corroborated by IDA localization to
      endocytic vesicle from the same gene.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      A soluble form of AMN arises by proteolytic removal of the membrane anchor and is secreted;
      this justifies an extracellular-region localization for that shed form. Peripheral, not the
      core membrane-bound function.
    action: KEEP_AS_NON_CORE
    reason: >-
      SubCell mapping is consistent with the documented secreted soluble AMN form, but the biologically
      central form is the membrane-anchored co-receptor. Keep as non-core.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: >-
        A soluble form arises by proteolytic removal of the membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      AMN is a single-pass type I plasma-membrane protein. Correct, though the more informative apical
      plasma membrane term better captures its polarized epithelial localization.
    action: ACCEPT
    reason: >-
      Consistent with EXP/TAS/IDA plasma-membrane annotations and UniProt SubCell Cell membrane.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      During receptor-mediated endocytosis AMN resides on the endosome membrane as cubam is
      internalized and recycled. Consistent with the endocytic itinerary.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by UniProt SubCell (Endosome membrane) and the endocytic role; a transit/recycling
      localization rather than the primary functional site.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Endosome membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Generic membrane localization; correct but uninformative relative to the specific
      apical/microvillus plasma-membrane terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but too general; the specific apical plasma membrane / microvillus membrane annotations
      carry the informative content.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Apical plasma membrane localization of AMN, from SubCell mapping. Matches the experimentally
      determined apical cell membrane localization; core localization.
    action: ACCEPT
    reason: >-
      Corroborated by IDA/NAS apical plasma membrane annotations and UniProt Apical cell membrane.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30523278
  qualifier: enables
  review:
    summary: >-
      This IPI records the AMN-CUBN interaction (with UniProtKB:O60494 = CUBN). "protein binding" is
      an uninformative bare term; the biologically meaningful content of this interaction is captured
      by AMN's cargo receptor activity (anchoring the cubilin subunits) rather than generic binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare protein binding is uninformative. The interaction it documents
      (AMN binding cubilin, structurally resolved) is real and central, but its functional meaning is
      already represented by cargo receptor activity and by the cubam complex membership. Retained as
      over-annotated rather than removed (experimental IPI).
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: >-
        we present the crystal structure of AMN in complex with the amino-terminal region of cubilin
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Endocytic vesicle localization transferred from rat ortholog; consistent with AMN's endocytic
      role and with the IDA/IBA endocytic vesicle annotations.
    action: ACCEPT
    reason: >-
      Ortholog-transferred localization agrees with experimental human annotations for the same term.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
- term:
    id: GO:0031526
    label: brush border membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Brush border (microvillus) membrane localization, consistent with cubam's site of action on the
      apical surface of ileal enterocytes and proximal tubule cells; matches the IDA microvillus
      membrane annotation.
    action: ACCEPT
    reason: >-
      Ortholog-transferred localization consistent with the experimentally determined microvillus
      membrane localization (PMID:14576052) and the apical epithelial role.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: >-
      AMN is part of the cubam protein complex (one AMN + three cubilin chains). Correct but generic;
      the specific cubam receptor complex is the informative description.
    action: KEEP_AS_NON_CORE
    reason: >-
      True (cubam is a defined protein complex, ComplexPortal CPX-5774) but the generic term is
      subsumed by the more specific complex membership; keep as non-core.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: >-
        we present the crystal structure of AMN in complex with the amino-terminal region of cubilin
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: involved_in
  review:
    summary: >-
      Cubam (AMN+cubilin) is the functional IF-cobalamin receptor: cells cotransfected with AMN and
      cubilin acquire IF-cobalamin endocytosis and lysosomal delivery. Core biological process for AMN.
    action: ACCEPT
    reason: >-
      Directly demonstrated: AMN is required to reconstitute IF-cobalamin uptake and degradation.
      This is a core function.
    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: >-
      Generic membrane localization; correct but uninformative relative to the specific apical/
      microvillus plasma-membrane terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but too general; superseded by the specific membrane subcompartment annotations.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: >-
      Apical plasma membrane localization (author statement). Consistent with the experimentally
      determined apical/microvillus localization; core site of action.
    action: ACCEPT
    reason: >-
      Concordant with IDA apical plasma membrane and UniProt Apical cell membrane.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: >-
      AMN localizes to endocytic vesicles as cubam internalizes ligand; documented colocalization in
      the endocytic apparatus of polarized epithelial cells.
    action: ACCEPT
    reason: >-
      Directly observed colocalization of AMN with cubilin in the endocytic apparatus.
    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: >-
      Records AMN's membership in the cubam receptor complex via its structurally resolved interaction
      with cubilin. However, cubam is an endocytic/cargo receptor, not a signaling receptor; the
      "signaling" qualifier is an over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The complex is real and central, but it is a nutrient-uptake endocytic receptor, not a signaling
      receptor complex. The accurate content is captured by cargo receptor activity and by cubam
      complex membership. Over-annotated rather than removed (experimental IPI documenting a genuine
      interaction).
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: >-
        we present the crystal structure of AMN in complex with the amino-terminal region of cubilin
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: >-
      Experimentally determined plasma-membrane localization of AMN. Core localization.
    action: ACCEPT
    reason: >-
      Direct experimental evidence; AMN is a plasma-membrane co-receptor subunit.
    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: >-
      Experimentally determined plasma-membrane localization; AMN is required for cubilin's own
      plasma-membrane expression, and AMN itself resides at the surface.
    action: ACCEPT
    reason: >-
      Direct experimental support for surface localization of the AMN/cubilin complex.
    supported_by:
    - reference_id: PMID:29402915
      supporting_text: amnionless-dependent membrane expression of cubilin
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:30523278
  qualifier: located_in
  review:
    summary: >-
      Plasma-membrane localization consistent with AMN being the transmembrane anchor of cubam
      (single-pass type I membrane protein).
    action: ACCEPT
    reason: >-
      Structural/biochemical study confirms AMN as the transmembrane subunit anchoring cubam to the
      membrane.
    supported_by:
    - reference_id: PMID:30523278
      supporting_text: >-
        anchors three ligand-binding cubilin subunits to the transmembrane AMN
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      AMN, as part of cubam, is required for intestinal absorption of vitamin B12, acting upstream of
      cobalamin metabolism. Reflects its role in supplying cobalamin to the body.
    action: ACCEPT
    reason: >-
      AMN loss causes B12 deficiency (IGS2); cubam-mediated uptake is the entry step for dietary
      cobalamin. Upstream-of relationship to cobalamin metabolism is appropriate.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
- term:
    id: GO:0031528
    label: microvillus membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: >-
      AMN localizes to the microvillus (brush border) membrane of polarized epithelia, the apical
      site where cubam captures its ligands.
    action: ACCEPT
    reason: >-
      Consistent with apical/brush-border localization of the cubam receptor in enterocytes and
      proximal tubule cells.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: enables
  review:
    summary: >-
      Direct experimental support for AMN's cargo receptor activity: reconstitution of AMN with the
      cubilin ligand-binding construct confers ligand endocytosis that neither protein alone provides.
      Core molecular function.
    action: ACCEPT
    reason: >-
      Neither AMN nor a truncated cubilin construct alone confers endocytosis; together they form the
      functional cargo receptor. This directly establishes AMN's cargo-receptor (co-receptor) function.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        neither protein alone conferred ligand endocytosis
- term:
    id: GO:0031528
    label: microvillus membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: is_active_in
  review:
    summary: >-
      AMN is active at the microvillus (brush border) membrane, the apical site of cubam-mediated
      ligand capture and internalization.
    action: ACCEPT
    reason: >-
      Consistent with the apical/brush-border localization and function of cubam.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: involved_in
  review:
    summary: >-
      AMN participates in cobalamin metabolism through cubam-mediated intestinal B12 uptake. Duplicate
      of the acts_upstream_of_or_within annotation with the same evidence.
    action: ACCEPT
    reason: >-
      Same experimental basis as the other cobalamin metabolic process annotation; AMN is required for
      cellular acquisition of vitamin B12.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: IMP
  original_reference_id: PMID:20088845
  qualifier: involved_in
  review:
    summary: >-
      Mutational analysis of AMN's two cytoplasmic FXNPXF signals shows they are required for
      internalization of cubam; simultaneous loss of both arrests ligand at the cell surface.
      Direct genetic (mutagenesis) support for receptor-mediated endocytosis.
    action: ACCEPT
    reason: >-
      IMP from FXNPXF signal mutants: both signals possess endocytic capability and are needed for
      cubam internalization via ARH/Dab2/clathrin. Core process.
    supported_by:
    - reference_id: PMID:20088845
      supporting_text: >-
        both FXNPXF signals in the cytosolic domain of AMN possess endocytic capabilities and that one
        signal is sufficient for uptake of labeled ligand via the cubam complex
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      AMN was detected by high-throughput proteomics of human urinary exosomes. This reflects shedding
      of the apical membrane protein into urinary exosomes from renal epithelia, not a functional
      site of action.
    action: KEEP_AS_NON_CORE
    reason: >-
      Proteomic detection in urinary exosomes is consistent with AMN's apical renal-epithelial
      expression but is a peripheral/incidental localization, not its functional site.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        we used LC-MS/MS to profile the proteome of human urinary exosomes
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:14576052
  qualifier: enables
  review:
    summary: >-
      This IPI (with CUBN, UniProtKB:O60494) records the AMN-cubilin interaction. Cubilin is a cargo
      receptor, not a signaling receptor, so "signaling receptor binding" mischaracterizes the
      interaction; the accurate description is co-receptor/cargo receptor assembly.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction with cubilin is genuine and central, but neither partner is a signaling receptor;
      the "signaling" framing is an over-annotation. The informative content is AMN's cargo receptor
      activity and cubam membership. Over-annotated rather than removed (experimental IPI documenting a
      real, structurally confirmed interaction).
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: >-
      A soluble form of AMN is secreted following proteolytic removal of the membrane anchor,
      accounting for extracellular-region localization. Peripheral relative to the membrane-bound
      co-receptor form.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the documented soluble/secreted AMN form; the biologically central form is the
      membrane-anchored co-receptor.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: >-
        A soluble form arises by proteolytic removal of the membrane
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: involved_in
  review:
    summary: >-
      Reconstitution of AMN with cubilin confers IF-cobalamin endocytosis and lysosomal degradation,
      directly demonstrating AMN's role in receptor-mediated endocytosis. Core process.
    action: ACCEPT
    reason: >-
      Direct experimental demonstration that AMN is required for cubam-mediated ligand endocytosis.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: located_in
  review:
    summary: >-
      Directly observed apical plasma membrane localization of AMN in polarized epithelial cells.
      Core localization.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for apical localization; consistent with UniProt Apical cell
      membrane.
    supported_by:
    - reference_id: file:human/AMN/AMN-uniprot.txt
      supporting_text: Apical cell membrane
- term:
    id: GO:0043001
    label: Golgi to plasma membrane protein transport
  evidence_type: IDA
  original_reference_id: PMID:14576052
  qualifier: involved_in
  review:
    summary: >-
      AMN is required to move cubilin from early biosynthetic compartments (ER/Golgi) to the cell
      surface; without AMN, cubilin accumulates intracellularly. This trafficking/chaperone role for
      its partner supports involvement in Golgi-to-plasma-membrane protein transport.
    action: ACCEPT
    reason: >-
      Experimentally supported: cubilin reaches the surface only when co-expressed with AMN, otherwise
      it is retained in early biosynthetic compartments. AMN thus enables secretory transport of the
      complex to the plasma membrane.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell
        surface and endosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3296477
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization of AMN at the plasma membrane in the context of cubam-mediated
      GIF:Cbl uptake (and its defect). Consistent with experimental localization.
    action: ACCEPT
    reason: >-
      Concordant with EXP/IDA plasma-membrane localization; Reactome models AMN as a plasma-membrane
      cubam subunit.
    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-264834
  qualifier: located_in
  review:
    summary: >-
      Reactome localization of AMN at the plasma membrane in the apoA-I endocytosis/degradation
      pathway (renal cubam reabsorption). Consistent with experimental localization.
    action: ACCEPT
    reason: >-
      Concordant with the experimentally supported plasma-membrane localization of the cubam subunit.
    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-264848
  qualifier: located_in
  review:
    summary: >-
      Reactome localization of AMN at the plasma membrane in the apoA-I binding step of cubam-mediated
      renal reabsorption. Consistent with experimental localization.
    action: ACCEPT
    reason: >-
      Concordant with experimental plasma-membrane localization; cubam acts on apical surfaces.
    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-3000103
  qualifier: located_in
  review:
    summary: >-
      Reactome localization of AMN at the plasma membrane where CUBN:AMN binds CBLIF:RCbl in the
      ileum. Consistent with experimental localization.
    action: ACCEPT
    reason: >-
      Concordant with experimental plasma-membrane localization of cubam.
    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-3000137
  qualifier: located_in
  review:
    summary: >-
      Reactome localization of AMN at the plasma membrane in CUBN:AMN-mediated CBLIF:RCbl uptake and
      lysosomal delivery. Consistent with experimental localization and endocytic recycling.
    action: ACCEPT
    reason: >-
      Concordant with experimental plasma-membrane localization; cubam returns to the plasma membrane
      after ligand delivery.
    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 localization of AMN at the plasma membrane in the defective-CUBN pathway (failed
      GIF:Cbl transport). Consistent with experimental localization.
    action: ACCEPT
    reason: >-
      Concordant with experimental plasma-membrane localization of the cubam subunit.
    supported_by:
    - reference_id: PMID:14576052
      supporting_text: >-
        cubilin trafficked to the cell surface and endosomes
core_functions:
- description: >-
    Membrane-anchoring/endocytic co-receptor subunit of the cubam receptor: AMN provides the
    transmembrane anchor and cytoplasmic endocytosis signals that ligand-binding cubilin lacks,
    functioning as a cargo receptor that internalizes cubilin-bound ligands.
  molecular_function:
    id: GO:0038024
    label: cargo receptor activity
  directly_involved_in:
  - id: GO:0006898
    label: receptor-mediated endocytosis
  supported_by:
  - reference_id: PMID:14576052
    supporting_text: >-
      neither protein alone conferred ligand endocytosis
  - reference_id: PMID:20088845
    supporting_text: >-
      both are able to mediate endocytosis of cubam through interaction with Dab2 and ARH
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  in_complex:
    id: GO:0043235
    label: receptor complex
- description: >-
    As part of cubam at the apical/microvillus membrane of ileal enterocytes, AMN mediates uptake of
    dietary vitamin B12 (cobalamin) complexed with intrinsic factor, and reabsorption of filtered
    proteins in the renal proximal tubule.
  molecular_function:
    id: GO:0038024
    label: cargo receptor activity
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  supported_by:
  - reference_id: PMID:14576052
    supporting_text: >-
      the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
  locations:
  - id: GO:0016324
    label: apical plasma membrane
references:
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:14576052
  title: The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel
    complex of cubilin and amnionless.
  findings:
  - statement: >-
      Cubilin and AMN form the cubam complex; AMN binds the amino-terminal third of cubilin and
      directs the subcellular localization and endocytosis of cubilin with its ligand. Neither
      protein alone confers ligand endocytosis; together they reconstitute IF-cobalamin uptake and
      lysosomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational paper defining cubam as CUBN+AMN and establishing AMN's role in localization and
      endocytosis. Cache is abstract-only but the abstract directly supports the annotations.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: >-
      Proteomic profiling of human urinary exosomes; AMN is among detected proteins, consistent with
      shedding of apical renal-epithelial membrane proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput proteomics source for the extracellular-exosome (HDA) localization; peripheral
      to AMN's core function.
- id: PMID:20088845
  title: AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam
    by engaging ARH or Dab2.
  findings:
  - statement: >-
      AMN provides membrane anchorage and endocytic capacity via two redundant FXNPXF cytoplasmic
      signals that engage the clathrin adaptors ARH and Dab2 to internalize cubam and its ligands.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text mechanistic study of AMN's endocytic signals; supports receptor-mediated endocytosis
      and the membrane-anchor/cargo-receptor role.
- id: PMID:29402915
  title: Amnionless-mediated glycosylation is crucial for cell surface targeting of
    cubilin in renal and intestinal cells.
  findings:
  - statement: >-
      AMN-dependent glycosylation and trafficking are required for cell-surface expression of cubilin;
      IGS-causing AMN missense mutations cause ER retention and abolish surface expression of cubilin.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text study establishing AMN's requirement for cubilin surface targeting; supports the
      trafficking/localization annotations and plasma-membrane localization.
- id: PMID:30523278
  title: Structural assembly of the megadalton-sized receptor for intestinal vitamin
    B(12) uptake and kidney protein reabsorption.
  findings:
  - statement: >-
      Crystal structure of AMN with the amino-terminal region of cubilin shows a single AMN chain
      anchoring three ligand-binding cubilin subunits to the membrane via a beta-helix-beta-helix
      docking.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Structural basis of cubam assembly and of AMN's membrane-anchoring role (PDB 6GJE); source of
      the AMN-CUBN IPI interaction.
- id: file:human/AMN/AMN-uniprot.txt
  title: UniProtKB Q9BXJ7 (AMNLS_HUMAN) entry
  findings:
  - statement: >-
      AMN is a single-pass type I membrane glycoprotein localized to the apical cell membrane; it is
      the membrane-bound component of the AMN+CUBN endocytic receptor. A soluble form arises by
      proteolytic removal of the membrane anchor.
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record used for topology, subcellular location, and the secreted soluble-form
      annotations.
- 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: []