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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:30523278 anchored to the apical membrane via interaction with the type-1 transmembrane protein amnionless (AMN) |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:20237569 how two distant CUB domains embrace the Cbl molecule by binding the two IF domains in a Ca(2+)-dependent manner |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Lysosome membrane |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | 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. 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). Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell electronic annotation to plasma membrane. Correct; cubilin is displayed at the cell surface as part of the AMN-anchored cubam complex. Reason: Consistent with experimental and phylogenetic annotations placing cubilin at the (apical) plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell electronic annotation to the generic membrane term. True but uninformative given the more specific apical/plasma membrane annotations. Reason: Correct as a high-level parent of the more specific (apical) plasma membrane localization. Retained but subsumed by more specific terms. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Peripheral membrane protein |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Apical plasma membrane is the defining site of cubilin function, well supported experimentally (IDA) and by orthology (ISS) as well as this IEA. Supporting Evidence: PMID:29402915 cubilin is secreted at the apical surface in a glycosylation-dependent process |
| GO:0030139 endocytic vesicle | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA (IEA) annotation to endocytic vesicle. Consistent with cubilin's role in receptor-mediated endocytosis and its experimentally documented endocytic-vesicle localization. Reason: Cubilin/cubam and cargo are internalized into endocytic vesicles; supported by the experimental IDA endocytic vesicle annotation for this gene. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells |
| GO:0031253 cell projection membrane | IEA GO_REF:0000117 | ACCEPT | 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. Reason: Consistent with the microvillus/brush-border membrane annotations; cell projection membrane is an accurate parent term for the microvilli of the brush border. Supporting Evidence: PMID:30523278 cubam location the enterocyte brush-border membrane |
| GO:0005515 protein binding | IPI PMID:20237569 Structural basis for receptor recognition of vitamin-B(12)-i... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:20237569 the crystal structure of the complex between IF-Cbl and the cubilin IF-Cbl-binding-region (CUB(5-8)) |
| GO:0005515 protein binding | IPI PMID:30523278 Structural assembly of the megadalton-sized receptor for int... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:30523278 combine into an intertwined Ξ²-helical structure that docks on to a corresponding Ξ²-helix domain in AMN |
| GO:0015889 cobalamin transport | TAS Reactome:R-HSA-9758881 | ACCEPT | 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. 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. Supporting Evidence: PMID:14576052 the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF |
| GO:0042359 vitamin D metabolic process | TAS Reactome:R-HSA-196791 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Acts together with LRP2 to mediate endocytosis of high-density |
| GO:0038024 cargo receptor activity | TAS Reactome:R-HSA-350186 | ACCEPT | 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. 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). Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Endocytic receptor which plays a role in lipoprotein, vitamin |
| GO:0015889 cobalamin transport | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Direct experimental evidence that cubam confers IF-cobalamin endocytosis; this is cubilin's canonical transport role. 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... | ACCEPT | Summary: ComplexPortal IDA annotation to the generic membrane term. Correct but subsumed by the more specific apical plasma / microvillus membrane annotations. Reason: Correct high-level location; cubilin is a peripheral membrane protein at the cell surface. Retained as a broad parent of more specific terms. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes |
| GO:0016324 apical plasma membrane | NAS PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Apical plasma membrane is the defining functional site of cubilin, supported by experimental localization in intestinal and renal epithelia. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes |
| GO:0030139 endocytic vesicle | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | Summary: ComplexPortal IDA annotation to endocytic vesicle, based on colocalization of cubilin and AMN in the endocytic apparatus and internalization of IF-cobalamin. Reason: Direct experimental support for endocytic-vesicle localization as part of the receptor-mediated endocytosis pathway. Supporting Evidence: PMID:14576052 cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells |
| GO:0030139 endocytic vesicle | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Consistent with the ComplexPortal endocytic-vesicle annotation; a genuine duplicate from a different assigning source. 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... | ACCEPT | 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. 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. Supporting Evidence: PMID:30523278 combine into an intertwined Ξ²-helical structure that docks on to a corresponding Ξ²-helix domain in AMN |
| GO:0038024 cargo receptor activity | EXP PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Direct experimental demonstration of cubilin as the ligand-binding subunit of an endocytic cargo receptor. 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:0038024 cargo receptor activity | EXP PMID:20237569 Structural basis for receptor recognition of vitamin-B(12)-i... | ACCEPT | 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. Reason: The structure defines the molecular basis of cubilin's cargo-receptor recognition of the IF-Cbl ligand, supporting the core MF. Supporting Evidence: PMID:20237569 the crystal structure of the complex between IF-Cbl and the cubilin IF-Cbl-binding-region (CUB(5-8)) |
| GO:0038024 cargo receptor activity | EXP PMID:30523278 Structural assembly of the megadalton-sized receptor for int... | ACCEPT | 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. Reason: Establishes cubilin as the multivalent ligand-binding component of the cubam endocytic receptor. Supporting Evidence: PMID:30523278 essential for intestinal vitamin B12 (B12) uptake and for protein (e.g. albumin) reabsorption from the kidney filtrate |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. Reason: Consistent with delivery of endocytosed ligands to lysosomes, but the defining functional location is the apical plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Lysosome membrane |
| GO:0005768 endosome | EXP PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Directly supported experimental endosomal localization consistent with cubilin's receptor-mediated endocytosis role. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes |
| GO:0005768 endosome | EXP PMID:29402915 Amnionless-mediated glycosylation is crucial for cell surfac... | ACCEPT | 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. Reason: Cubilin is internalized from the apical surface into the endocytic/endosomal compartment; experimentally supported. Supporting Evidence: PMID:29402915 mini-cubilin was internalised from the apical surface |
| GO:0005886 plasma membrane | EXP PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Direct experimental evidence for plasma-membrane (cell-surface) localization of cubilin as part of the cubam complex. 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: 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. Reason: Direct experimental support for AMN-dependent plasma-membrane localization. Supporting Evidence: PMID:29402915 when cubilin was co-expressed with amnionless, a fraction of cubilin expressed at the plasma membrane was detected |
| GO:0005886 plasma membrane | EXP PMID:30523278 Structural assembly of the megadalton-sized receptor for int... | ACCEPT | Summary: Experimental annotation to plasma membrane from the cubam structural-assembly study, which established that cubilin is anchored to the apical membrane via AMN. Reason: Cubilin is displayed at the (apical) plasma membrane through AMN anchoring; experimentally supported. Supporting Evidence: PMID:30523278 anchored to the apical membrane via interaction with the type-1 transmembrane protein amnionless (AMN) |
| GO:0016324 apical plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation to apical plasma membrane by transfer from rodent ortholog (Q9JLB4). Consistent with the core apical localization of cubilin. Reason: Apical plasma membrane is the core functional location, well supported experimentally and by orthology. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate ISS annotation to apical plasma membrane, transferred from a second rodent ortholog (O70244). Consistent with the core apical localization of cubilin. Reason: Genuine duplicate of the apical plasma membrane ISS from a different ortholog; apical plasma membrane is the core functional location. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0009235 cobalamin metabolic process | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:14576052 intestinal cobalamin (vitamin B(12)) malabsorption |
| GO:0031528 microvillus membrane | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Microvillus (brush border) membrane is a precise and correct description of cubilin's apical localization in absorptive epithelia. Supporting Evidence: PMID:30523278 cubam location the enterocyte brush-border membrane |
| GO:0038024 cargo receptor activity | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | Summary: MGI IDA annotation for cargo receptor activity, from the demonstration that cubam confers IF-cobalamin endocytosis. Core molecular function. Reason: Direct experimental evidence for cubilin's cargo/endocytic receptor function. 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:0038024 cargo receptor activity | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: Genuine duplicate of the MGI cargo receptor activity IDA; direct experimental support for cubilin's cargo/endocytic receptor function. 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:0031528 microvillus membrane | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | 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. Reason: The microvillus (brush border) membrane is where cubilin performs its ligand-capture function; correct and precise active-site localization. Supporting Evidence: PMID:30523278 cubam location the enterocyte brush-border membrane |
| GO:0009235 cobalamin metabolic process | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:14576052 intestinal cobalamin (vitamin B(12)) malabsorption |
| GO:0043235 signaling receptor complex | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Cubilin is genuinely part of the cubam receptor complex with AMN; complex membership is accurate even though the "signaling" qualifier is imprecise. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Component of the cubam complex |
| GO:0038024 cargo receptor activity | TAS PMID:9478979 The intrinsic factor-vitamin B12 receptor and target of tera... | ACCEPT | 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. Reason: The founding characterization of cubilin identified it as the endocytic receptor facilitating IF-B12 uptake, the basis for its cargo-receptor MF. Supporting Evidence: PMID:9478979 functions as the receptor facilitating uptake of intrinsic factor-vitamin B12 complexes in the intestine and kidney |
| GO:0031526 brush border membrane | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Brush border membrane is a precise, correct description of cubilin's apical localization; supported experimentally and by orthology. Supporting Evidence: PMID:30523278 cubam location the enterocyte brush-border membrane |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure |
| GO:0070062 extracellular exosome | IDA PMID:21082674 Comprehensive analysis of low-abundance proteins in human ur... | KEEP AS NON CORE | 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. Reason: Consistent with cubilin's presence in urinary exosomes shed from renal epithelia; a non-functional localization observation. Supporting Evidence: PMID:21082674 relatively low-abundant proteins in urinary exosomes |
| GO:0005515 protein binding | IPI PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:14576052 cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput proteomics (HDA) detection of cubilin in the human urinary-exosome proteome. Reflects shedding into urinary exosomes rather than a functional site. Reason: Consistent with cubilin's abundance at the apical surface of renal epithelia and its shedding into urinary exosomes; a non-functional localization observation. Supporting Evidence: PMID:19056867 profile the proteome of human urinary exosomes |
| GO:0016324 apical plasma membrane | IDA PMID:14576052 The functional cobalamin (vitamin B12)-intrinsic factor rece... | ACCEPT | Summary: UniProt IDA annotation to apical plasma membrane. Core functional location of cubilin as displayed on polarized epithelial apical surfaces. Reason: Apical plasma membrane is the defining functional site of cubilin; experimentally supported. Supporting Evidence: PMID:14576052 cubilin trafficked to the cell surface and endosomes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3296462 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (from a defective-CUBN transport reaction). Correct high-level location subsumed by the apical plasma membrane annotations. Reason: Correct as a broad location for the cell-surface receptor; retained as parent of apical plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0005829 cytosol | TAS Reactome:R-HSA-209760 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Lacks a transmembrane domain and depends on |
| GO:0005829 cytosol | TAS Reactome:R-HSA-350168 | MARK AS OVER ANNOTATED | 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. Reason: Cubilin is not a cytosolic protein; this reflects Reactome pathway modeling rather than genuine localization. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Lacks a transmembrane domain and depends on |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-209760 | KEEP AS NON CORE | 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. Reason: Endocytosed ligands and cubilin can be delivered to the lysosome for degradation; a valid downstream location but not the core functional site. Supporting Evidence: PMID:14576052 lysosomal degradation of IF |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-350158 | KEEP AS NON CORE | 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. Reason: Consistent with delivery of cubilin-bound cargo to the lysosome; downstream, non-core. Supporting Evidence: PMID:14576052 lysosomal degradation of IF |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-264834 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (endocytosis/degradation of apoA-I reaction). Correct broad cell-surface location. Reason: Cubilin at the plasma membrane captures apoA-I/HDL for endocytosis; correct broad location subsumed by apical plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Acts together with LRP2 to mediate endocytosis of high-density |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-264848 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (apoA-I binds CUBN:AMN reaction). Correct broad cell-surface location. Reason: Consistent with cubilin's cell-surface (apical) localization where it binds apoA-I; retained as broad parent term. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3000103 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (CUBN:AMN binds CBLIF:RCbl reaction). Correct broad cell-surface location where IF-cobalamin is captured. Reason: Correct broad location; cubam binds IF-cobalamin at the (apical) plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3000137 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (CUBN:AMN-mediated CBLIF:RCbl uptake reaction). Correct broad cell-surface location. Reason: Consistent with cubam-mediated IF-cobalamin uptake at the cell surface; retained as broad parent of apical plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3296477 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (defective-AMN transport reaction). Correct broad cell-surface location. Reason: Correct broad location for the cubam receptor at the cell surface. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-350168 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (LRP2-mediated uptake of extracellular CUBN:GC:25(OH)D reaction). Correct broad cell-surface location. Reason: Consistent with cubilin's cell-surface localization; retained as broad parent of apical plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-350186 | ACCEPT | Summary: Reactome TAS annotation to plasma membrane (CUBN binds GC:25(OH)D reaction). Correct broad cell-surface location. Reason: Correct broad location where cubilin binds vitamin-D-binding protein for reabsorption; retained as parent of apical plasma membrane. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Apical cell membrane |
| GO:0001894 tissue homeostasis | NAS PMID:11994745 Megalin and cubilin: multifunctional endocytic receptors. | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:11994745 Megalin and cubilin are two structurally different endocytic receptors that interact to serve such functions |
| GO:0006898 receptor-mediated endocytosis | NAS PMID:11994745 Megalin and cubilin: multifunctional endocytic receptors. | ACCEPT | 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. Reason: Receptor-mediated endocytosis is the defining biological process of cubilin, well supported across the literature. Supporting Evidence: PMID:11994745 Megalin and cubilin are two structurally different endocytic receptors that interact to serve such functions |
| GO:0031232 extrinsic component of external side of plasma membrane | NAS PMID:11994745 Megalin and cubilin: multifunctional endocytic receptors. | ACCEPT | 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. 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. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Lacks a transmembrane domain and depends on |
| GO:0031526 brush border membrane | NAS PMID:11994745 Megalin and cubilin: multifunctional endocytic receptors. | ACCEPT | Summary: NAS annotation to brush border membrane. Cubilin is a brush-border receptor of absorptive epithelia; a specific and correct apical location. Reason: Brush border membrane accurately describes cubilin's apical localization in intestinal and renal epithelia. Supporting Evidence: PMID:30523278 cubam location the enterocyte brush-border membrane |
| GO:0042803 protein homodimerization activity | IDA PMID:10552972 Genetic evidence of an accessory activity required specifica... | UNDECIDED | 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. 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. Supporting Evidence: PMID:30523278 potential of dimerization into an even larger complex |
| GO:0015889 cobalamin transport | TAS PMID:10080186 Mutations in CUBN, encoding the intrinsic factor-vitamin B12... | ACCEPT | 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. Reason: Genetic evidence that CUBN loss causes selective intestinal B12 malabsorption directly supports cubilin's role in cobalamin transport. Supporting Evidence: PMID:10080186 MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption |
| GO:0016020 membrane | TAS PMID:9478979 The intrinsic factor-vitamin B12 receptor and target of tera... | ACCEPT | Summary: PINC TAS annotation to the generic membrane term, from the original characterization of cubilin as a peripheral membrane receptor. Correct but high-level. Reason: Correct as a broad location; cubilin is a peripheral membrane protein. Subsumed by more specific apical/brush-border membrane terms. Supporting Evidence: PMID:9478979 a megalin-binding peripheral membrane protein |
| GO:0038023 signaling receptor activity | TAS PMID:10080186 Mutations in CUBN, encoding the intrinsic factor-vitamin B12... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/CUBN/CUBN-uniprot.txt Endocytic receptor which plays a role in lipoprotein, vitamin |
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