AMN

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016324 apical plasma membrane	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells file:human/AMN/AMN-uniprot.txt Apical cell membrane
GO:0038024 cargo receptor activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:20088845 cubilin contains no transmembrane segment and therefore needs the transmembrane region of AMN to be anchored in the plasma membrane
GO:0043235 signaling receptor complex	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	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. 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 Sources checked: PANTHER:PTN001029969 · AMN family node UniProtKB:Q9BXJ7 · AMN (human) Supporting Evidence: PMID:20088845 Cubam is a multi-ligand receptor involved in dietary uptake of intrinsic factor-vitamin file:human/AMN/AMN-uniprot.txt Membrane-bound component of the endocytic receptor formed by
GO:0097017 renal protein absorption	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:20088845 cubam is involved in reabsorption of various proteins from the glomerular ultrafiltrate
GO:0006898 receptor-mediated endocytosis	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:20088845 both are able to mediate endocytosis of cubam through interaction with Dab2 and ARH
GO:0008104 intracellular protein localization	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:14576052 AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand
GO:0030139 endocytic vesicle	IBA GO_REF:0000033	ACCEPT	Summary: Cubam is internalized into and cycles through endocytic vesicles; AMN is active there during cargo internalization and receptor recycling. Reason: Consistent with the receptor-mediated endocytosis role and corroborated by IDA localization to endocytic vesicle from the same gene. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
GO:0005576 extracellular region	IEA GO_REF:0000044	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/AMN/AMN-uniprot.txt A soluble form arises by proteolytic removal of the membrane
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	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. Reason: Consistent with EXP/TAS/IDA plasma-membrane annotations and UniProt SubCell Cell membrane. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Single-pass type I membrane protein
GO:0010008 endosome membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: During receptor-mediated endocytosis AMN resides on the endosome membrane as cubam is internalized and recycled. Consistent with the endocytic itinerary. Reason: Supported by UniProt SubCell (Endosome membrane) and the endocytic role; a transit/recycling localization rather than the primary functional site. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Endosome membrane
GO:0016020 membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Generic membrane localization; correct but uninformative relative to the specific apical/microvillus plasma-membrane terms. Reason: True but too general; the specific apical plasma membrane / microvillus membrane annotations carry the informative content. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Single-pass type I membrane protein
GO:0016324 apical plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Apical plasma membrane localization of AMN, from SubCell mapping. Matches the experimentally determined apical cell membrane localization; core localization. Reason: Corroborated by IDA/NAS apical plasma membrane annotations and UniProt Apical cell membrane. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Apical cell membrane
GO:0005515 protein binding	IPI PMID:30523278 Structural assembly of the megadalton-sized receptor for int...	MARK AS OVER ANNOTATED	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. 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). Supporting Evidence: PMID:30523278 we present the crystal structure of AMN in complex with the amino-terminal region of cubilin
GO:0030139 endocytic vesicle	IEA GO_REF:0000107	ACCEPT	Summary: Endocytic vesicle localization transferred from rat ortholog; consistent with AMN's endocytic role and with the IDA/IBA endocytic vesicle annotations. Reason: Ortholog-transferred localization agrees with experimental human annotations for the same term. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
GO:0031526 brush border membrane	IEA GO_REF:0000107	ACCEPT	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. Reason: Ortholog-transferred localization consistent with the experimentally determined microvillus membrane localization (PMID:14576052) and the apical epithelial role. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
GO:0032991 protein-containing complex	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:30523278 we present the crystal structure of AMN in complex with the amino-terminal region of cubilin
GO:0015889 cobalamin transport	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	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. Reason: Directly demonstrated: AMN is required to reconstitute IF-cobalamin uptake and degradation. This is a core function. Supporting Evidence: PMID:14576052 the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
GO:0016020 membrane	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	KEEP AS NON CORE	Summary: Generic membrane localization; correct but uninformative relative to the specific apical/ microvillus plasma-membrane terms. Reason: True but too general; superseded by the specific membrane subcompartment annotations. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Single-pass type I membrane protein
GO:0016324 apical plasma membrane	NAS PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: Apical plasma membrane localization (author statement). Consistent with the experimentally determined apical/microvillus localization; core site of action. Reason: Concordant with IDA apical plasma membrane and UniProt Apical cell membrane. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Apical cell membrane
GO:0030139 endocytic vesicle	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: AMN localizes to endocytic vesicles as cubam internalizes ligand; documented colocalization in the endocytic apparatus of polarized epithelial cells. Reason: Directly observed colocalization of AMN with cubilin in the endocytic apparatus. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
GO:0043235 signaling receptor complex	IPI PMID:30523278 Structural assembly of the megadalton-sized receptor for int...	MARK AS OVER ANNOTATED	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. 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). Supporting Evidence: PMID:30523278 we present the crystal structure of AMN in complex with the amino-terminal region of cubilin
GO:0005886 plasma membrane	EXP PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: Experimentally determined plasma-membrane localization of AMN. Core localization. Reason: Direct experimental evidence; AMN is a plasma-membrane co-receptor subunit. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	EXP PMID:29402915 Amnionless-mediated glycosylation is crucial for cell surfac...	ACCEPT	Summary: Experimentally determined plasma-membrane localization; AMN is required for cubilin's own plasma-membrane expression, and AMN itself resides at the surface. Reason: Direct experimental support for surface localization of the AMN/cubilin complex. Supporting Evidence: PMID:29402915 amnionless-dependent membrane expression of cubilin
GO:0005886 plasma membrane	EXP PMID:30523278 Structural assembly of the megadalton-sized receptor for int...	ACCEPT	Summary: Plasma-membrane localization consistent with AMN being the transmembrane anchor of cubam (single-pass type I membrane protein). Reason: Structural/biochemical study confirms AMN as the transmembrane subunit anchoring cubam to the membrane. Supporting Evidence: PMID:30523278 anchors three ligand-binding cubilin subunits to the transmembrane AMN
GO:0009235 cobalamin metabolic process	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	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. 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. Supporting Evidence: PMID:14576052 the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
GO:0031528 microvillus membrane	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: AMN localizes to the microvillus (brush border) membrane of polarized epithelia, the apical site where cubam captures its ligands. Reason: Consistent with apical/brush-border localization of the cubam receptor in enterocytes and proximal tubule cells. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
GO:0038024 cargo receptor activity	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	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. 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. Supporting Evidence: PMID:14576052 neither protein alone conferred ligand endocytosis
GO:0031528 microvillus membrane	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: AMN is active at the microvillus (brush border) membrane, the apical site of cubam-mediated ligand capture and internalization. Reason: Consistent with the apical/brush-border localization and function of cubam. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells
GO:0009235 cobalamin metabolic process	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	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. Reason: Same experimental basis as the other cobalamin metabolic process annotation; AMN is required for cellular acquisition of vitamin B12. Supporting Evidence: PMID:14576052 the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
GO:0006898 receptor-mediated endocytosis	IMP PMID:20088845 AMN directs endocytosis of the intrinsic factor-vitamin B(12...	ACCEPT	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. Reason: IMP from FXNPXF signal mutants: both signals possess endocytic capability and are needed for cubam internalization via ARH/Dab2/clathrin. Core process. Supporting Evidence: PMID:20088845 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
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes
GO:0005102 signaling receptor binding	IPI PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	MARK AS OVER ANNOTATED	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. 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). Supporting Evidence: PMID:14576052 cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex
GO:0005576 extracellular region	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	KEEP AS NON CORE	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. Reason: Supported by the documented soluble/secreted AMN form; the biologically central form is the membrane-anchored co-receptor. Supporting Evidence: file:human/AMN/AMN-uniprot.txt A soluble form arises by proteolytic removal of the membrane
GO:0006898 receptor-mediated endocytosis	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: Reconstitution of AMN with cubilin confers IF-cobalamin endocytosis and lysosomal degradation, directly demonstrating AMN's role in receptor-mediated endocytosis. Core process. Reason: Direct experimental demonstration that AMN is required for cubam-mediated ligand endocytosis. Supporting Evidence: PMID:14576052 the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF
GO:0016324 apical plasma membrane	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	Summary: Directly observed apical plasma membrane localization of AMN in polarized epithelial cells. Core localization. Reason: Direct experimental evidence for apical localization; consistent with UniProt Apical cell membrane. Supporting Evidence: file:human/AMN/AMN-uniprot.txt Apical cell membrane
GO:0043001 Golgi to plasma membrane protein transport	IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece...	ACCEPT	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. 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. Supporting Evidence: PMID:14576052 in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3296477	ACCEPT	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. Reason: Concordant with EXP/IDA plasma-membrane localization; Reactome models AMN as a plasma-membrane cubam subunit. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-264834	ACCEPT	Summary: Reactome localization of AMN at the plasma membrane in the apoA-I endocytosis/degradation pathway (renal cubam reabsorption). Consistent with experimental localization. Reason: Concordant with the experimentally supported plasma-membrane localization of the cubam subunit. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-264848	ACCEPT	Summary: Reactome localization of AMN at the plasma membrane in the apoA-I binding step of cubam-mediated renal reabsorption. Consistent with experimental localization. Reason: Concordant with experimental plasma-membrane localization; cubam acts on apical surfaces. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3000103	ACCEPT	Summary: Reactome localization of AMN at the plasma membrane where CUBN:AMN binds CBLIF:RCbl in the ileum. Consistent with experimental localization. Reason: Concordant with experimental plasma-membrane localization of cubam. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3000137	ACCEPT	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. Reason: Concordant with experimental plasma-membrane localization; cubam returns to the plasma membrane after ligand delivery. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3296462	ACCEPT	Summary: Reactome localization of AMN at the plasma membrane in the defective-CUBN pathway (failed GIF:Cbl transport). Consistent with experimental localization. Reason: Concordant with experimental plasma-membrane localization of the cubam subunit. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

📚 Additional Documentation

Notes

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