Folate receptor alpha is a GPI-anchored cell-surface receptor of epithelial tissues that captures folate and reduced folates with high affinity at neutral pH and carries them into the cell. Because the anchor sits in the outer leaflet, the entire folate-binding domain faces the extracellular space and is accessible on intact cells, which is the basis of folate-targeted imaging and therapy. Bound receptor is internalised through clathrin-coated vesicles into endosomes, where mildly acidic pH triggers a conformational change that releases the folate, and the receptor is then recycled to the surface. In polarised epithelia it is sorted apically or basolaterally depending on the tissue, and it contributes to folate supply during embryonic development; loss-of-function mutations cause cerebral folate transport deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001947 heart looping | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A folate-dependent developmental process documented in the mouse ortholog. Reason: Transferred from mouse Folr1, where loss causes severe developmental defects. The receptor's contribution is to supply folate rather than to execute cardiac morphogenesis, so the term is retained as non-core. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0001947 heart looping | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same mouse phenotype. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0003147 neural crest cell migration involved in heart formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Folate deficiency and Folr1 loss disturb cardiac neural crest in rodents. Reason: Ortholog-derived developmental role, downstream of folate supply rather than a direct activity of the receptor. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0003147 neural crest cell migration involved in heart formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same role. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0003253 cardiac neural crest cell migration involved in outflow tract morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A more specific version of the same ortholog-derived cardiac neural crest role. Reason: Same assessment as the other neural crest rows; the receptor supplies folate to migrating cells rather than driving migration itself. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0003253 cardiac neural crest cell migration involved in outflow tract morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same role. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: An SLC35F6 hit from a proteome-scale binary interactome map. Reason: The generic term carries no functional information, and a single high-throughput interaction supports no specific molecular function for a GPI-anchored folate receptor. Removal does not assert that the interaction was not detected. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt P15328; Q8N357 |
| GO:0005542 folic acid binding | IDA PMID:10787414 Expression and differential polarization of the reduced-fola... | ACCEPT | Summary: Folate binding is the defining activity of this receptor. Reason: The study works with folate receptor alpha in retinal pigment epithelium and its folate-handling function; binding is established directly in several other studies and structurally. Supporting Evidence: PMID:23851396 To understand how folate binds its receptors, we determined the crystal structure of human FRΞ± in complex with folic acid at 2.8 Γ
resolution. |
| GO:0005542 folic acid binding | IDA PMID:14722620 Translational upregulation of folate receptors is mediated b... | ACCEPT | Summary: Folate-binding activity of the receptor is measured in this work on receptor regulation. Reason: Consistent with the curated high-affinity folate binding of FOLR1. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Has high affinity for folate and folic acid analogs at neutral pH |
| GO:0005542 folic acid binding | IDA PMID:19116913 Folate receptor beta as a potential delivery route for novel... | ACCEPT | Summary: Folate and antifolate binding by folate receptors measured directly. Reason: The study compares folate receptor binding of novel antifolates, which depends on this activity. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Binds to folate and reduced folic acid derivatives |
| GO:0005542 folic acid binding | IDA PMID:23851396 Structural basis for molecular recognition of folic acid by ... | ACCEPT | Summary: The crystal structure of human folate receptor alpha with folic acid defines the binding site. Reason: Direct structural evidence for the molecular function. Supporting Evidence: PMID:23851396 To understand how folate binds its receptors, we determined the crystal structure of human FRΞ± in complex with folic acid at 2.8 Γ
resolution. |
| GO:0005542 folic acid binding | IDA PMID:2527252 Complementary DNA for the folate binding protein correctly p... | ACCEPT | Summary: The cloned folate binding protein binds folate and is GPI-anchored. Reason: The original characterisation of the folate binding protein supports this molecular function. Supporting Evidence: PMID:2527252 Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol. |
| GO:0005542 folic acid binding | NAS PMID:1840502 Cloning of a tumor-associated antigen: MOv18 and MOv19 antib... | ACCEPT | Summary: The MOv18 and MOv19 tumour antigen was identified as a folate-binding protein. Reason: Independently established by direct binding and structural studies. Supporting Evidence: PMID:1840502 Cloning of a tumor-associated antigen, MOv18 and MOv19 antibodies recognize a folate-binding protein. |
| GO:0005542 folic acid binding | TAS PMID:9545095 Lack of association between mutations in the folate receptor... | ACCEPT | Summary: Author statement of folate binding in a spina bifida genetics study. Reason: Independently established by the structural and biochemical work. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Has high affinity for folate and folic acid analogs at neutral pH |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A soluble form released from the GPI anchor is found extracellularly. Reason: UniProt records a secreted form alongside the membrane-anchored receptor, and soluble folate binding protein is detectable in body fluids. The functional pool is the membrane-anchored receptor, so this is retained as non-core. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Secreted {ECO |
| GO:0005634 nucleus | IDA PMID:23243496 Nuclear localization of folate receptor alpha: a new role as... | KEEP AS NON CORE | Summary: A reported nuclear pool acting as a transcription factor. Reason: The cited study reports translocation of folate receptor alpha to the nucleus and binding to promoter elements. This is a single, surprising claim for a GPI-anchored protein and is not reflected in the curated UniProt locations, so it is retained as non-core rather than accepted as a core location. Supporting Evidence: PMID:23243496 The work described here shows that FRΞ± translocates to the nucleus, where it binds to cis-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression. |
| GO:0005768 endosome | EXP PMID:8567728 Endocytosis of GPI-linked membrane folate receptor-alpha. | ACCEPT | Summary: Immunoelectron microscopy places the receptor throughout the endocytic pathway. Reason: Endosomal residence is mechanistically central, because the acidic endosomal pH triggers the conformational change that releases folate before the receptor recycles. Supporting Evidence: PMID:8567728 Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway, in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping of the curated endosome location. Reason: Faithful to the experimental evidence for receptor recycling through endosomes. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Note=Endocytosed into cytoplasmic vesicles and then recycled to the cell membrane. |
| GO:0005886 plasma membrane | EXP PMID:2527252 Complementary DNA for the folate binding protein correctly p... | ACCEPT | Summary: The folate binding protein is anchored in the membrane by GPI. Reason: A GPI anchor attaches the receptor to the outer leaflet of the plasma membrane, which is the core functional location. Supporting Evidence: PMID:2527252 Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol. |
| GO:0005886 plasma membrane | EXP PMID:8033114 UMSCC38 cells amplified at 11q13 for the folate receptor syn... | ACCEPT | Summary: Functional and mutant receptors were studied at the cell membrane. Reason: UniProt cites this study for the cell-membrane location, and folate transport measured on intact cells requires surface receptor. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005886 plasma membrane | EXP PMID:8567728 Endocytosis of GPI-linked membrane folate receptor-alpha. | ACCEPT | Summary: Internalised receptor recycles back to the cell surface. Reason: The endocytosis study follows the receptor from the plasma membrane and back, establishing the surface pool directly. Supporting Evidence: PMID:8567728 Internalized MFR-alpha recycled slowly to the cell surface during which it remained soluble in Triton X-100 at 0 degree C. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Folate receptors act at the plasma membrane. Reason: The ancestral assertion matches the human protein, which captures extracellular folate at the cell surface before internalisation. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping of the curated cell-membrane location. Reason: Consistent with the extensive experimental evidence. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Lipid-anchor, GPI-anchor |
| GO:0005886 plasma membrane | NAS PMID:1840502 Cloning of a tumor-associated antigen: MOv18 and MOv19 antib... | ACCEPT | Summary: The tumour antigen recognised by MOv18 is a membrane folate binding protein. Reason: Consistent with the curated GPI-anchored cell-membrane location. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Lipid-anchor, GPI-anchor |
| GO:0006898 receptor-mediated endocytosis | TAS PMID:9545095 Lack of association between mutations in the folate receptor... | ACCEPT | Summary: Folate uptake by this receptor proceeds through endocytosis. Reason: The receptor is internalised in clathrin-coated vesicles with its ligand and recycles after release, which is exactly this process, and the GO definition of folic acid receptor activity names endocytic delivery. Supporting Evidence: PMID:8567728 Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway, in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. |
| GO:0009897 external side of plasma membrane | IDA PMID:2527252 Complementary DNA for the folate binding protein correctly p... | ACCEPT | Summary: The GPI anchor holds the receptor on the outer leaflet, with the whole folate-binding domain extracellular. Reason: This is the most precise statement of the protein's topology and explains why it is accessible to folate conjugates and antibodies on intact cells. Supporting Evidence: PMID:2527252 Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol. |
| GO:0009897 external side of plasma membrane | IDA PMID:8033114 UMSCC38 cells amplified at 11q13 for the folate receptor syn... | ACCEPT | Summary: Receptor function was assayed from outside intact cells. Reason: Folate binding and transport measured on intact cells require an outward-facing receptor. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Lipid-anchor, GPI-anchor |
| GO:0009986 cell surface | HDA PMID:19581412 Quantitative proteomics identifies a Dab2/integrin module re... | ACCEPT | Summary: FOLR1 is recovered in cell-surface proteomic analyses. Reason: Consistent with the GPI-anchored outward-facing topology established experimentally. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Lipid-anchor, GPI-anchor |
| GO:0015884 folic acid transport | IBA GO_REF:0000033 | ACCEPT | Summary: Delivering folate into cells is the core biological role of this receptor. Reason: The receptor binds folate outside the cell and carries it inward by endocytosis, performing the capture and delivery steps of this transport process. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells |
| GO:0015884 folic acid transport | IMP PMID:8033114 UMSCC38 cells amplified at 11q13 for the folate receptor syn... | ACCEPT | Summary: A mutant receptor in UMSCC38 cells is non-functional for folate transport. Reason: Loss-of-function evidence in human cells directly ties the receptor to folate uptake. Supporting Evidence: PMID:8033114 UMSCC38 cells amplified at 11q13 for the folate receptor synthesize a mutant nonfunctional folate receptor. |
| GO:0015884 folic acid transport | TAS PMID:9545095 Lack of association between mutations in the folate receptor... | ACCEPT | Summary: Author statement of the folate transport role. Reason: Independently established by the mutant-receptor and endocytosis studies. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells |
| GO:0016020 membrane | TAS PMID:10633085 Interaction of folate receptor with signaling molecules lyn ... | MODIFY | Summary: Correct but less specific than the evidence allows. Reason: The receptor is GPI-anchored in the plasma membrane, a term it already carries with experimental support, and the detergent-resistant complexes studied here are plasma-membrane microdomains. Proposed replacements: plasma membrane Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Lipid-anchor, GPI-anchor |
| GO:0016020 membrane | TAS PMID:2768245 Molecular cloning and characterization of the human folate-b... | MODIFY | Summary: The cloning paper describes a membrane folate binding protein. Reason: The specific plasma-membrane term is supported and already carried by the gene. Proposed replacements: plasma membrane Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0016323 basolateral plasma membrane | IDA PMID:10787414 Expression and differential polarization of the reduced-fola... | ACCEPT | Summary: In retinal pigment epithelium the receptor is basolateral. Reason: Confocal microscopy shows a basolateral distribution of folate receptor alpha in cultured human and intact mouse RPE, in contrast to the apical reduced-folate transporter. Supporting Evidence: PMID:10787414 Laser-scanning confocal microscopy using antibodies specific for RFT-1 demonstrated an apical distribution of this protein in cultured human and intact mouse RPE, which contrasts with the basolateral distribution of FRalpha in these cells. |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping of the curated basolateral cell membrane location. Reason: UniProt records both apical and basolateral locations with experimental evidence, reflecting tissue-specific sorting of the GPI-anchored receptor. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Basolateral cell membrane |
| GO:0016324 apical plasma membrane | IDA PMID:10787414 Expression and differential polarization of the reduced-fola... | ACCEPT | Summary: Apical sorting is seen in other polarised epithelia. Reason: UniProt records an apical cell membrane location with experimental evidence from this study, alongside the basolateral pool; GPI-anchored proteins are canonically apically sorted, with tissue-specific exceptions. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping of the curated apical cell membrane location. Reason: Faithful to the curated record. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Apical cell membrane |
| GO:0017015 regulation of transforming growth factor beta receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: An ortholog-derived signalling association. Reason: No human evidence, and the link is most plausibly indirect, through folate supply and one-carbon metabolism rather than a direct action of the receptor on TGF beta signalling. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0017015 regulation of transforming growth factor beta receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same association. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0030136 clathrin-coated vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: The receptor is internalised in clathrin-coated vesicles. Reason: Immunoelectron microscopy detects the receptor in clathrin-coated buds and vesicles, and UniProt records the location on experimental evidence. Supporting Evidence: PMID:8567728 Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway, in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. |
| GO:0031103 axon regeneration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A rodent-derived role in regenerating neurons. Reason: Folate supply supports regeneration, but the evidence is from the ortholog and the receptor's contribution is to deliver folate rather than to drive axon growth. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0031103 axon regeneration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same role. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0031410 cytoplasmic vesicle | EXP PMID:8567728 Endocytosis of GPI-linked membrane folate receptor-alpha. | ACCEPT | Summary: Internalised receptor is found in cytoplasmic vesicles. Reason: Part of the endocytic recycling itinerary that delivers folate into the cell. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Note=Endocytosed into cytoplasmic vesicles and then recycled to the cell membrane. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping of the curated cytoplasmic vesicle location. Reason: Faithful to the experimental endocytosis data. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Note=Endocytosed into cytoplasmic vesicles and then recycled to the cell membrane. |
| GO:0031526 brush border membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: An ortholog-derived apical membrane specialisation in absorptive epithelia. Reason: Consistent with apical sorting of the GPI-anchored receptor in some epithelia, but not demonstrated for the human protein, so it is kept as non-core. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Apical cell membrane |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: FOLR1 is a cargo receptor that internalises folate, not a signalling receptor. Reason: The GO definition of folic acid receptor activity, combining selectively with extracellular folic acid and delivering it into the cell via endocytosis, is exactly what this protein does, and that term sits under cargo receptor activity rather than signaling receptor activity. The family node assertion is therefore mis-scoped for this branch. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000054892 SUPPORTS SOURCE BUT NOT TARGET The node asserts a signalling receptor role for the folate receptor family, whereas the activity these receptors perform is cargo capture and endocytic delivery. Proposed replacements: folic acid receptor activity Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells |
| GO:0038023 signaling receptor activity | TAS PMID:10633085 Interaction of folate receptor with signaling molecules lyn ... | MODIFY | Summary: Association with Lyn and G alpha i-3 in detergent-resistant membranes does not establish signalling receptor activity. Reason: The cited work shows that the GPI-anchored receptor co-resides with signalling molecules in membrane microdomains, which is common for GPI-anchored proteins and does not show ligand-triggered signal transduction by FOLR1 itself. The supported molecular function is folate capture and endocytic delivery. Proposed replacements: folic acid receptor activity Supporting Evidence: PMID:10633085 Interaction of folate receptor with signaling molecules lyn and G(alpha)(i-3) in detergent-resistant complexes from the ovary carcinoma cell line IGROV1. |
| GO:0046654 tetrahydrofolate biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The receptor imports folates; it does not catalyse any step of tetrahydrofolate synthesis. Reason: Reduction of folate to tetrahydrofolate is carried out by dihydrofolate reductase, while FOLR1 delivers 5-methyltetrahydrofolate and other folates into the cell. Supplying the substrate is not participation in the biosynthetic process; the transport role is recorded separately. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells |
| GO:0048678 response to axon injury | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: An ortholog-derived association with injured neurons. Reason: Related to the axon regeneration rows and equally indirect; retained as non-core. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0060828 regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: An ortholog-derived signalling association. Reason: No human evidence, and the most likely mechanism is indirect through folate availability and methylation rather than a direct action of the receptor on Wnt signalling. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0060828 regulation of canonical Wnt signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same association. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0061626 pharyngeal arch artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Part of the folate-dependent cardiac neural crest programme seen in rodents. Reason: Ortholog-derived and downstream of folate supply. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0061626 pharyngeal arch artery morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same role. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0061713 anterior neural tube closure | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Folate receptor loss in mice causes neural tube defects. Reason: The best-known folate-dependent developmental process, but the receptor's contribution is folate delivery, and the human genetic evidence for FOLR1 in neural tube defects is weak, with no association found in the spina bifida study cited elsewhere in this review. Supporting Evidence: PMID:9545095 Lack of association between mutations in the folate receptor-alpha gene and spina bifida. |
| GO:0061713 anterior neural tube closure | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same mouse phenotype. Reason: Same assessment as the Compara row. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Required for normal embryonic development and normal cell proliferation |
| GO:0061714 folic acid receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Capturing extracellular folate and delivering it into the cell by endocytosis is the core molecular function. Reason: The ancestral assertion matches the human protein exactly, and human FOLR1 has its own structural and functional evidence for high-affinity folate binding and endocytic delivery. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells |
| GO:0061714 folic acid receptor activity | IC GO_REF:0000036 | ACCEPT | Summary: Curator inference from the other annotations, consistent with the biology. Reason: The combination of high-affinity folate binding at the cell surface and pH-dependent release in endosomes is precisely this activity. Supporting Evidence: PMID:8567728 Internalized MFR-alpha recycled slowly to the cell surface during which it remained soluble in Triton X-100 at 0 degree C. |
| GO:0061714 folic acid receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer agreeing with the direct human evidence. Reason: Human and rodent folate receptors share this activity. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Has high affinity for folate and folic acid analogs at neutral pH |
| GO:0061714 folic acid receptor activity | IMP PMID:8033114 UMSCC38 cells amplified at 11q13 for the folate receptor syn... | ACCEPT | Summary: A naturally occurring mutant receptor fails to perform folate uptake. Reason: Loss-of-function evidence in human cells directly supports the activity. Supporting Evidence: PMID:8033114 UMSCC38 cells amplified at 11q13 for the folate receptor synthesize a mutant nonfunctional folate receptor. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: FOLR1 is identified in parotid gland exosome proteomes. Reason: GPI-anchored surface proteins are routinely recovered in exosome preparations; the detection carries no functional information. Supporting Evidence: PMID:19199708 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Also recovered in prostatic exosome proteomes. Reason: Same assessment as the other exosome row. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0071231 cellular response to folic acid | IDA PMID:14722620 Translational upregulation of folate receptors is mediated b... | KEEP AS NON CORE | Summary: Receptor expression is regulated by folate and homocysteine status. Reason: The cited work shows translational upregulation of folate receptors mediated by homocysteine, which is a response of the gene to one-carbon status rather than an activity of the protein. Retained as non-core. Supporting Evidence: PMID:14722620 Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-6809006 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-6809010 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-6809011 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-203973 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-204008 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5694410 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5694417 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5694522 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5694527 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-203973 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-5694409 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-5694418 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-5694439 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-5694441 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0012507 ER to Golgi transport vesicle membrane | TAS Reactome:R-HSA-5694446 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-6807877 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-6809003 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-6809006 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | TAS Reactome:R-HSA-5694446 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | TAS Reactome:R-HSA-6807875 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | TAS Reactome:R-HSA-6807877 | KEEP AS NON CORE | Summary: A compartment on the biosynthetic and GPI-anchoring route of this GPI-anchored receptor. Reason: Reactome models attachment and remodelling of the GPI anchor and the transport of the precursor towards the cell surface. The compartment is correct for the maturing protein, but folate binding and uptake happen at the plasma membrane and in the endocytic recycling pathway. Supporting Evidence: file:human/FOLR1/FOLR1-uniprot.txt Cell membrane {ECO |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: What determines whether the GPI-anchored receptor is sorted apically or basolaterally, given that retinal pigment epithelium places it basolaterally while other epithelia place it apically?
Q: Is the reported nuclear, transcription-factor role of folate receptor alpha reproducible, and if so how does a GPI-anchored ectoprotein reach the nucleoplasm?
Q: How much of the folate taken up by human epithelia depends on FOLR1 endocytosis versus the reduced folate carrier and PCFT transporters?
Experiment: Express the same tagged FOLR1 construct in polarised RPE and in intestinal or kidney epithelial monolayers, and compare domain-specific surface biotinylation with and without perturbation of sphingolipid synthesis.
Hypothesis: Apical versus basolateral sorting of FOLR1 depends on tissue-specific lipid raft composition rather than on the protein itself.
Experiment: Repeat the nuclear localisation and promoter-binding experiments with endogenous tagged FOLR1 in a knock-in line, with GPI-anchor-deficient and signal-peptide-deficient controls, and test chromatin occupancy by CUT and RUN.
Hypothesis: The nuclear pool of folate receptor alpha is an artefact of the antibody or of overexpression.
Experiment: Measure folate uptake flux in cells expressing wild-type FOLR1 while clamping endosomal pH pharmacologically, and compare with receptor variants altered in their pH-dependent release.
Hypothesis: Endosomal acidification, not receptor affinity, sets the rate of folate delivery.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)