TFRC encodes transferrin receptor protein 1 (TfR1/CD71), the major cell-surface receptor for cellular iron import. It is a homodimeric type II transmembrane glycoprotein that preferentially binds diferric (holo-)transferrin and internalizes the ligand-receptor complex via clathrin/AP-2-mediated endocytosis; iron is released in acidic endosomes (pH <= 5.5) and the apo-transferrin/TfR1 complex is recycled to the plasma membrane, completing the cycle in approximately 10-20 minutes. Internalization depends on the cytoplasmic tyrosine-based YTRF motif, and germline variants affecting this region cause an internalization defect and combined immunodeficiency, identifying TfR1 as a non-redundant immune-metabolic checkpoint that supplies iron for lymphocyte proliferation and mitochondrial metabolism. A proteolytically shed soluble ectodomain (sTfR) circulates and serves as a clinical biomarker of iron demand/erythropoiesis. TfR1 is also exploited pathologically as an entry receptor by several viruses/pathogens and is a leading target for receptor-mediated transcytosis across the blood-brain barrier and for CD71-based cancer-targeted delivery.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006826 iron ion transport | IBA GO_REF:0000033 | ACCEPT | Summary: TfR1 is the major cell-surface receptor mediating cellular iron import by binding diferric transferrin and internalizing the ligand-receptor complex. Iron ion transport is a correct high-level process term for this receptor. Reason: Core biological process supported by phylogenetic inference and directly corroborated by falcon deep research describing TfR1-mediated iron import. Supporting Evidence: file:human/TFRC/TFRC-deep-research-perplexity.md See deep research file for comprehensive analysis file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0006879 intracellular iron ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: By controlling the rate of transferrin-bound iron import into the cell, TfR1 is a central determinant of intracellular iron levels, and its own expression is feedback-regulated by cellular iron status via IRE/IRP control of its mRNA. Reason: Core process consistent with phylogenetic inference and the receptor's defining iron-import function; corroborated by deep research describing TfR1 as the major receptor for cellular iron import. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TfR1 is a type II transmembrane protein whose large C-terminal ectodomain (residues 89-760) faces the extracellular space, where it binds holo-transferrin at the cell surface. The external side of plasma membrane is the correct location for the ligand-binding ectodomain. Reason: Consistent with UniProt topology (extracellular ligand-binding domain) and with the cell-surface receptor function supported by phylogenetic inference. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: TfR1 is exploited as a cell-entry receptor by several pathogens, including New World hemorrhagic fever arenaviruses (Machupo, Junin, Guanarito), rabies virus, and Plasmodium vivax reticulocyte invasion. This term captures the host-factor role in symbiont/pathogen entry. Reason: A genuine but pathogen-exploited (non-core) role distinct from the physiological iron-uptake function; supported by experimental structural studies of arenavirus and P. vivax interactions with TfR1 and by UniProt microbial-infection annotations. Supporting Evidence: PMID:20208545 The GP1 subunit of the surface glycoprotein mediates cell attachment through transferrin receptor 1 (TfR1) PMID:29302006 Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax |
| GO:0001618 virus receptor activity | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Human TfR1 serves as a cell-surface entry receptor for several viruses, including New World hemorrhagic fever arenaviruses (which engage the apical TfR1 domain via their GP1 glycoprotein) and rabies virus. This is a bona fide virus receptor activity. Reason: Well-documented but pathogen-exploited (non-core) molecular function distinct from the physiological transferrin receptor activity; structurally demonstrated for arenaviruses and annotated for rabies/SARS-CoV-2 in UniProt. Supporting Evidence: PMID:20208545 The GP1 subunit of the surface glycoprotein mediates cell attachment through transferrin receptor 1 (TfR1) |
| GO:0004998 transferrin receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Transferrin receptor activity is the core molecular function of TFRC. The homodimeric receptor preferentially binds diferric (holo-)transferrin and internalizes the ligand-receptor complex for iron delivery. Reason: Defining molecular function, also supported by multiple IDA annotations and corroborated by falcon deep research. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin file:human/TFRC/TFRC-deep-research-falcon.md preferentially binds diferric transferrin |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A proteolytically shed soluble ectodomain of TfR1 (sTfR) circulates in serum, consistent with localization to the extracellular region. This is a broad UniProt subcellular-location mapping that captures the shed soluble form. Reason: Correct broad location for the shed soluble receptor (sTfR) rather than the core membrane receptor; supported by characterization of the released soluble receptor in serum/culture medium. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TfR1 is a type II transmembrane glycoprotein localized at the plasma membrane, where it binds diferric transferrin at the cell surface before internalization. Reason: Primary subcellular location of the receptor, supported by extensive IDA/TAS evidence and corroborated by falcon deep research describing TfR1 as a cell-surface receptor. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0006897 endocytosis | IEA GO_REF:0000043 | MODIFY | Summary: TfR1 is internalized with its transferrin ligand by clathrin-mediated endocytosis. This is a high-level parent of the more specific receptor-mediated endocytosis term that is also annotated. Reason: Correct but more general than warranted; the specific mechanism is clathrin/AP-2 receptor-mediated endocytosis, which is independently annotated. Replace with the more informative child term. Proposed replacements: receptor-mediated endocytosis Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0006898 receptor-mediated endocytosis | IEA GO_REF:0000117 | ACCEPT | Summary: TfR1 internalizes diferric transferrin via clathrin/AP-2-mediated endocytosis, a canonical example of receptor-mediated endocytosis central to the iron uptake cycle. Reason: Well-established trafficking mechanism, also supported by IDA evidence and by falcon deep research describing the clathrin/AP-2 endocytic cycle. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0007165 signal transduction | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: This very general process term is assigned from UniProt keyword mapping. While TfR1 has reported signaling roles (e.g. modulating JNK signaling via stearoylation and contributing to IKK-NF-kB signaling), the bare "signal transduction" term is uninformative and not a core function. Reason: Over-general keyword-derived term; the receptor's defining role is iron uptake, and its specific signaling contributions (JNK regulation, NF-kB) are better captured by the dedicated IMP annotations rather than a bare signal-transduction term. Supporting Evidence: PMID:23016877 Taken together, these results indicate a new function for TfR1 in the control of IKK and NF-ΞΊB. |
| GO:0033572 transferrin transport | IEA GO_REF:0000120 | ACCEPT | Summary: TfR1 mediates transferrin transport by binding holo-transferrin, internalizing it, releasing iron in acidic endosomes, and recycling apo-transferrin back to the cell surface. Reason: Core process consistent with the transferrin endocytic recycling cycle described in falcon deep research. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: TfR1 has been detected in melanosome proteomes, the basis for this UniProt location mapping. This likely reflects co-purification of endosomal/recycling membranes with melanosomes rather than a dedicated melanosomal function. Reason: Derived from high-throughput melanosome proteomics; not a core localization but plausible given TfR1's broad presence on endosomal/recycling membranes that overlap with the melanosome maturation pathway. Retained as non-core. |
| GO:0060586 multicellular organismal-level iron ion homeostasis | IEA GO_REF:0000117 | ACCEPT | Summary: Beyond cell-autonomous iron handling, TfR1 contributes to organism-level iron homeostasis: TfR1-knockout mice die in utero with severe anemia, and TfR1 participates in the HFE/TfR2 hepcidin-regulatory axis sensing body iron status. Reason: Supported experimentally by the requirement of TfR1 for erythropoiesis in vivo and by its role in the HFE-dependent iron-sensing system; also independently annotated by IDA (PMID:26642240). Supporting Evidence: PMID:10192390 Transferrin receptor is necessary for development of erythrocytes and the nervous system. |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TFRC is a well-established HIF target gene whose expression is induced under hypoxia (it contains a functional hypoxia-response element), consistent with a response to hypoxia. This term was transferred from experimentally annotated orthologs. Reason: Biologically plausible (TFRC is HIF-regulated and induced by hypoxia) but a regulatory/response role downstream of the core iron-uptake function rather than a defining activity; retained as non-core. |
| GO:0005615 extracellular space | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The shed soluble transferrin receptor (sTfR) is released into serum and the extracellular space, consistent with this localization. Reason: Reflects the shed soluble ectodomain rather than the membrane receptor's core function; supported by characterization of the released soluble receptor. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. |
| GO:0005768 endosome | IEA GO_REF:0000107 | ACCEPT | Summary: TfR1 traffics through endosomes during the transferrin cycle, where iron is released at acidic pH before receptor recycling. Endosome is a correct location. Reason: Core compartment of the iron-release/recycling cycle; consistent with multiple IDA endosome annotations and with the trafficking cycle described in deep research. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0005769 early endosome | IEA GO_REF:0000107 | ACCEPT | Summary: After clathrin-mediated internalization, the TfR1-transferrin complex traffics to acidic (early) endosomes where iron is released at pH <= 5.5 before receptor recycling. Reason: Consistent with the endosomal step of the iron-release cycle described in falcon deep research. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0005905 clathrin-coated pit | IEA GO_REF:0000107 | ACCEPT | Summary: TfR1 concentrates in clathrin-coated pits as cargo for clathrin/AP-2-mediated endocytosis, the entry point of the iron uptake cycle. Reason: Consistent with the clathrin/AP-2 endocytic mechanism described in falcon deep research and with the IDA clathrin-coated pit annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0006953 acute-phase response | IEA GO_REF:0000107 | REMOVE | Summary: This term was transferred from an ortholog. There is no strong direct evidence that human TfR1 functions in the acute-phase response; TFRC expression is more directly tied to iron status, proliferation, and hypoxia than to acute-phase inflammation. Reason: Weakly supported ortholog-transferred annotation with no specific human experimental backing; not part of the receptor's established functional repertoire and risks over-annotation. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TFRC expression and surface levels respond to the cell's nutrient/iron status, broadly consistent with a response to nutrient. This is an ortholog-transferred term subsumed by the more specific response-to-iron annotation. Reason: Plausible but generic response term that is better captured by the specific response-to-iron-ion annotation; retained as non-core. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TfR1 is a type II transmembrane protein whose large C-terminal ectodomain faces the extracellular space and binds holo-transferrin at the cell surface. The external side of plasma membrane is the correct location for the ligand-binding ectodomain. Reason: Consistent with UniProt topology and the cell-surface receptor function; duplicates the accepted IBA annotation of the same term. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0009986 cell surface | IEA GO_REF:0000120 | ACCEPT | Summary: TfR1 (CD71) is a canonical cell-surface receptor displayed on the plasma membrane, where it binds circulating holo-transferrin. Reason: Defining surface localization of the receptor; also supported by ISS/IDA cell surface annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0010039 response to iron ion | IEA GO_REF:0000107 | ACCEPT | Summary: TFRC mRNA contains iron-responsive elements (IREs) in its 3' UTR; under iron depletion, IRP1/IRP2 binding stabilizes the transcript and increases receptor expression, while iron repletion lowers it. TfR1 expression is thus directly responsive to cellular iron levels. Reason: Well-established IRE/IRP-mediated regulation of TFRC by iron status makes response to iron ion a genuine and informative process annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-perplexity.md The 3β² untranslated region (3β² UTR) of TFRC mRNA contains five IREs, which are short conserved stem-loop structures recognized by two functionally similar iron regulatory proteins, IRP1 and IRP2 |
| GO:0010042 response to manganese ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This response-to-metal term was transferred from an ortholog. TfR1 can mediate cellular uptake of non-transferrin metals (TfR1 endocytoses Mn-loaded transferrin), but there is little direct human evidence for a dedicated manganese-response role. Reason: Weakly-supported ortholog-transferred response term, peripheral to the receptor's core iron-uptake function; retained as non-core rather than removed because TfR1 can transport manganese-bound transferrin. |
| GO:0016020 membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: TfR1 is an integral membrane protein. "Membrane" is a correct but very general location that is subsumed by the more specific plasma-membrane and endosome-membrane annotations. Reason: Uninformatively broad cellular-component term; more specific membrane locations (plasma membrane, endosome membrane, recycling endosome membrane) are annotated. |
| GO:0030316 osteoclast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Iron uptake via TfR1 has been implicated in osteoclast differentiation and bone metabolism, the basis for this ortholog-transferred term. This is a downstream, tissue-specific consequence of iron supply rather than a core receptor function. Reason: Plausible developmental/differentiation role secondary to iron delivery, but not a defining molecular activity; retained as non-core. |
| GO:0030544 Hsp70 protein binding | IEA GO_REF:0000107 | REMOVE | Summary: This molecular-function term was transferred from an ortholog. There is no robust direct human evidence that TfR1 itself binds Hsp70; HSPA8/HSC70 acts on the clathrin coat during vesicle uncoating rather than binding TfR1 directly. Reason: Weakly-supported ortholog-transferred molecular-function annotation lacking direct human experimental evidence for a TfR1-Hsp70 interaction; risks over-annotation. |
| GO:0032526 response to retinoic acid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TFRC expression can be modulated by retinoic acid during differentiation, the basis for this ortholog-transferred response term. This is a peripheral transcriptional response, not a core receptor function. Reason: Generic differentiation-related response term transferred from an ortholog; peripheral to the core iron-uptake function and retained as non-core. |
| GO:0046688 response to copper ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This response-to-metal term was transferred from an ortholog. There is little direct human evidence linking TfR1 specifically to a copper-ion response distinct from general iron/metal handling. Reason: Weakly-supported ortholog-transferred response term peripheral to the receptor's core iron-uptake function; retained as non-core. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: TfR1-positive recycling endosomes concentrate in the perinuclear endocytic recycling compartment, consistent with this localization. Also supported by IDA annotations. Reason: The perinuclear endocytic recycling compartment is a canonical TfR1 localization; corroborated by IDA perinuclear annotations (PMID:16380373, PMID:20202662). |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000107 | REMOVE | Summary: This molecular-function term was transferred from an ortholog and lacks direct human evidence that TfR1 binds protein-folding chaperones; the chaperone HSPA8 functions on the clathrin coat during uncoating rather than on TfR1 itself. Reason: Weakly-supported ortholog-transferred term without direct human experimental support; over-annotation analogous to the Hsp70-binding entry. |
| GO:0055037 recycling endosome | IEA GO_REF:0000120 | ACCEPT | Summary: Following iron release in acidic endosomes, the apo-transferrin/TfR1 complex is recycled back to the plasma membrane via recycling endosomes, completing the ~10-20 minute transferrin cycle. Reason: TfR1 is a canonical recycling-endosome marker; supported by falcon deep research describing receptor recycling to the surface. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0055038 recycling endosome membrane | IEA GO_REF:0000107 | ACCEPT | Summary: As an integral membrane protein recycled via recycling endosomes, TfR1 resides in the recycling endosome membrane during the transferrin cycle. Reason: Consistent with the canonical TfR1 recycling pathway; complements the accepted recycling endosome annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0070062 extracellular exosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TfR1 is a well-known marker of exosomes/extracellular vesicles, secreted during reticulocyte maturation when the receptor is shed via the multivesicular-body/exosome pathway. Detection in exosome proteomes is well documented. Reason: Genuine but secondary localization reflecting exosomal sorting of TfR1 during reticulocyte maturation; not the core membrane-receptor function. Retained as non-core. |
| GO:0098794 postsynapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TfR1-positive recycling endosomes are present in dendritic spines/postsynaptic compartments, where they supply membrane and traffic neurotransmitter receptors. This term derives from ortholog transfer of neuronal recycling-endosome studies. Reason: TfR1 marks postsynaptic recycling endosomes in neurons, a tissue-specific localization secondary to its general recycling-endosome role; retained as non-core. |
| GO:0098944 postsynaptic recycling endosome membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TfR1 marks recycling endosomes in postsynaptic compartments of neurons. This term was transferred from an ortholog and is a specialized, neuron-specific instance of the recycling endosome membrane localization. Reason: Tissue-specific (neuronal) recycling-endosome localization secondary to the general recycling function; retained as non-core. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TfR1 localizes to glutamatergic synapses via its presence in dendritic recycling endosomes that traffic AMPA-type glutamate receptors. This SynGO-style localization was transferred from an ortholog. Reason: Neuron-specific synaptic localization secondary to the general recycling-endosome role; retained as non-core. |
| GO:0099072 regulation of postsynaptic membrane neurotransmitter receptor levels | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TfR1-positive recycling endosomes contribute to trafficking of postsynaptic neurotransmitter (e.g. AMPA) receptors, influencing their surface levels. This process term was transferred from an ortholog. Reason: Neuron-specific process secondary to the general recycling-endosome function; not a core role of the iron receptor and retained as non-core. |
| GO:1990712 HFE-transferrin receptor complex | IEA GO_REF:0000107 | ACCEPT | Summary: TfR1 forms a stable complex with the hemochromatosis protein HFE; the crystal structure shows a 2:1 TfR:HFE stoichiometry, and HFE binding lowers TfR1's affinity for transferrin, linking TfR1 to systemic iron sensing. Reason: Well-documented protein complex supported by IDA structural and biochemical studies (also annotated by IDA from PMID:9546397, PMID:9465039, PMID:9990067). Supporting Evidence: PMID:9546397 TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2) |
| GO:0005515 protein binding | IPI PMID:14691533 Mechanism for multiple ligand recognition by the human trans... | MODIFY | Summary: This IPI captures binding of TfR1 to its ligands (transferrin, HFE, HFE2/hemojuvelin), characterized structurally/biochemically. The bare "protein binding" term is uninformative; the specific, informative function is transferrin receptor activity. Reason: Avoid endorsing bare protein binding; the experiment characterizes ligand recognition by the receptor, best captured by transferrin receptor activity. Proposed replacements: transferrin receptor activity Supporting Evidence: PMID:14691533 Cell surface TfR binds to circulating iron-loaded transferrin (Fe-Tf) and transports it to acidic endosomes |
| GO:0005515 protein binding | IPI PMID:15965644 The Q283P amino-acid change in HFE leads to structural and f... | MODIFY | Summary: This IPI reflects the TfR1-HFE interaction studied via the HFE Q283P variant. The bare "protein binding" term is uninformative; the specific outcome is formation of the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the documented interaction is with HFE, best captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:9546397 HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin |
| GO:0005515 protein binding | IPI PMID:16271884 The molecular mechanism for receptor-stimulated iron release... | MODIFY | Summary: This IPI documents TfR1 binding to transferrin and the receptor's active role in stimulating iron release at endosomal pH. The bare "protein binding" term is uninformative; the specific function is transferrin receptor activity. Reason: Avoid endorsing bare protein binding; the study characterizes the receptor's transferrin-binding and iron-release-promoting activity. Proposed replacements: transferrin receptor activity Supporting Evidence: PMID:16271884 Human transferrin receptor 1 (TfR) binds iron-loaded transferrin (Fe-Tf) and transports it to acidic endosomes where iron is released in a TfR-facilitated process |
| GO:0005515 protein binding | IPI PMID:16325581 TTP specifically regulates the internalization of the transf... | MARK AS OVER ANNOTATED | Summary: This IPI reflects the interaction between TfR1 and the endocytic adaptor TTP/SH3BP4, which selectively regulates TfR1 internalization through TfR-containing clathrin-coated pits and vesicles. The bare "protein binding" is uninformative. Reason: Avoid endorsing bare protein binding; the biologically informative aspect (regulated receptor internalization) is captured by the GO:0031623 receptor internalization annotation. The bare binding term itself is non-informative. Supporting Evidence: PMID:16325581 TTP (SH3BP4), a SH3-containing protein, specifically regulates the internalization of the transferrin receptor (TfR) |
| GO:0005515 protein binding | IPI PMID:16354665 Release of the soluble transferrin receptor is directly regu... | MODIFY | Summary: This IPI reflects TfR1 binding its ligand ferritransferrin (holo-transferrin), which regulates proteolytic shedding of the soluble receptor. The bare "protein binding" term is uninformative; the specific function is transferrin receptor activity. Reason: Avoid endorsing bare protein binding; the documented interaction is ligand binding by the receptor, best captured by transferrin receptor activity. Proposed replacements: transferrin receptor activity Supporting Evidence: PMID:16354665 sTfR release decreases with increasing ferritransferrin concentrations, whereas apo-transferrin exhibits no inhibitory effect |
| GO:0005515 protein binding | IPI PMID:20133674 Binding and uptake of H-ferritin are mediated by human trans... | MARK AS OVER ANNOTATED | Summary: This IPI reflects TfR1 binding and internalizing H-chain ferritin (HFt), an additional ligand recognized by the apical domain distinct from the transferrin site. The bare "protein binding" term is uninformative; the experiment demonstrates a specific ligand-binding/uptake function. Reason: Avoid endorsing bare protein binding; the H-ferritin uptake activity is a genuine but non-core additional ligand-binding role, and the bare binding term is uninformative. Supporting Evidence: PMID:20133674 we identified human transferrin receptor-1 (TfR1) as an important receptor for HFt with little or no binding to LFt |
| GO:0005515 protein binding | IPI PMID:20404192 Noncanonical interactions between serum transferrin and tran... | MODIFY | Summary: This IPI documents transferrin-TfR1 interactions characterized by native mass spectrometry. The bare "protein binding" term is uninformative; the specific function is transferrin receptor activity. Reason: Avoid endorsing bare protein binding; the interaction studied is ligand binding by the receptor, best captured by transferrin receptor activity. Proposed replacements: transferrin receptor activity Supporting Evidence: PMID:20404192 Noncanonical interactions between serum transferrin and transferrin receptor |
| GO:0005515 protein binding | IPI PMID:20618438 N-glycosylation is important for the correct intracellular l... | MODIFY | Summary: This IPI reflects the functional interaction between HFE and TfR1, whereby HFE decreases cell-surface transferrin binding by TfR1. The bare "protein binding" term is uninformative; the specific complex is the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the documented HFE-TfR1 interaction is better captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:20618438 its ability to decrease cell surface transferrin binding |
| GO:0005515 protein binding | IPI PMID:21788477 How the binding of human transferrin primes the transferrin ... | MODIFY | Summary: This IPI documents transferrin binding to TfR1 and how it primes the receptor to potentiate iron release at endosomal pH. The bare "protein binding" term is uninformative; the specific function is transferrin receptor activity. Reason: Avoid endorsing bare protein binding; the study characterizes ligand binding and the receptor's iron-release-promoting activity, best captured by transferrin receptor activity. Proposed replacements: transferrin receptor activity Supporting Evidence: PMID:21788477 How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH |
| GO:0005515 protein binding | IPI PMID:23384347 The transferrin receptor-1 membrane stub undergoes intramemb... | MARK AS OVER ANNOTATED | Summary: This IPI reflects processing of the TfR1 membrane stub (left after ectodomain shedding) by the intramembrane protease SPPL2b. The bare "protein binding" term describes TfR1 as a protease substrate rather than conferring an informative molecular function. Reason: Avoid endorsing bare protein binding; this captures TfR1 as a substrate of SPPL2b, a peripheral processing event, and the bare binding term is uninformative. Supporting Evidence: PMID:23384347 The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: This IPI derives from a high-throughput proteome-scale interactome (Y2H) screen. Such screens report binary interactions without functional context, and the bare "protein binding" term is uninformative. Reason: High-throughput interactome hit lacking specific functional interpretation; bare protein binding is non-informative and not a core function. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:29302006 Transferrin receptor 1 is a reticulocyte-specific receptor f... | MARK AS OVER ANNOTATED | Summary: This IPI reflects binding of TfR1 to the Plasmodium vivax ligand PvRBP2b during reticulocyte invasion. The bare "protein binding" term is uninformative; the biologically meaningful role (host receptor for pathogen entry) is captured by the symbiont-entry/virus-receptor annotations. Reason: Avoid endorsing bare protein binding; this host-pathogen interaction is informative only as a pathogen-entry receptor role, already annotated, and the bare binding term is non-informative. Supporting Evidence: PMID:29302006 Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. |
| GO:0005515 protein binding | IPI PMID:29950717 Cryo-EM structure of an essential Plasmodium vivax invasion ... | MARK AS OVER ANNOTATED | Summary: This IPI reflects the cryo-EM-resolved interaction between TfR1 and the P. vivax invasion ligand (PvRBP2b/transferrin complex). The bare "protein binding" term is uninformative; the meaningful role (pathogen-entry receptor) is annotated elsewhere. Reason: Avoid endorsing bare protein binding; this host-pathogen structural interaction is captured by the pathogen-entry receptor annotations and the bare term is non-informative. Supporting Evidence: PMID:29950717 Cryo-EM structure of an essential Plasmodium vivax invasion complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: This IPI derives from a high-throughput binary interactome (HuRI) reference map. Such screens report binary interactions without functional context, and the bare "protein binding" term is uninformative. Reason: High-throughput interactome hit lacking specific functional interpretation; bare protein binding is non-informative and not a core function. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0042802 identical protein binding | IPI PMID:20208545 Structural basis for receptor recognition by New World hemor... | ACCEPT | Summary: TfR1 functions as a homodimer, and the arenavirus GP1 structural study resolved TfR1 in its dimeric form. Identical protein binding (homodimerization) is consistent with the receptor's architecture. Reason: TfR1 is a well-characterized disulfide-linked homodimer; identical protein binding is correct and complements the protein homodimerization activity annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md homodimeric transmembrane glycoprotein |
| GO:0042802 identical protein binding | IPI PMID:23384347 The transferrin receptor-1 membrane stub undergoes intramemb... | ACCEPT | Summary: TfR1 is a homodimer; the SPPL2b processing study examined the dimeric receptor. Identical protein binding (homodimerization) is consistent with the receptor's architecture. Reason: TfR1 is a well-characterized homodimer; identical protein binding is correct and complements the protein homodimerization activity annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md homodimeric transmembrane glycoprotein |
| GO:0042802 identical protein binding | IPI PMID:29302006 Transferrin receptor 1 is a reticulocyte-specific receptor f... | ACCEPT | Summary: TfR1 is a homodimer, engaged in its dimeric form during P. vivax reticulocyte invasion studies. Identical protein binding (homodimerization) is consistent with the receptor's architecture. Reason: TfR1 is a well-characterized homodimer; identical protein binding is correct and complements the protein homodimerization activity annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md homodimeric transmembrane glycoprotein |
| GO:0004998 transferrin receptor activity | IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer... | ACCEPT | Summary: Direct assay of cell-associated transferrin demonstrated TfR1's transferrin-binding (receptor) activity, modulated by HFE. This is the core molecular function. Reason: Defining molecular function with direct experimental support; HFE overexpression measurably altered the receptor's transferrin affinity. Supporting Evidence: PMID:9465039 the overexpressed wild-type HFE protein decreases the affinity of the TfR for transferrin |
| GO:0006898 receptor-mediated endocytosis | IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer... | ACCEPT | Summary: TfR1 internalizes transferrin via receptor-mediated (clathrin-dependent) endocytosis, the basis of the iron-uptake cycle assayed here. Reason: Core trafficking process directly supported and duplicated by the accepted IEA receptor-mediated endocytosis annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer... | REMOVE | Summary: PMID:9465039 characterizes the HFE-TfR complex and its effect on transferrin affinity; it does not demonstrate a classical cell-surface receptor signaling cascade. TfR1 is primarily an endocytic/transport receptor rather than a signaling receptor, although it modulates JNK and NF-kB pathways in other studies. Reason: The cited paper does not support a canonical signaling pathway role; TfR1's documented signaling effects (JNK, NF-kB) are better captured by the specific IMP annotations. This generic term is over-annotation for this reference. Supporting Evidence: PMID:9465039 both the wild-type and H63D HFE proteins form stable complexes with the transferrin receptor (TfR) |
| GO:0033572 transferrin transport | IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer... | ACCEPT | Summary: TfR1 mediates uptake and transport of transferrin-bound iron, assayed via cell-associated transferrin in this study. Reason: Core process of the receptor; directly supported and consistent with the transferrin endocytic recycling cycle. Supporting Evidence: PMID:9465039 Studies on cell-associated transferrin at 37 degrees C suggest that the overexpressed wild-type HFE protein decreases the affinity of the TfR for transferrin |
| GO:0004998 transferrin receptor activity | IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul... | ACCEPT | Summary: This study assayed transferrin binding and transferrin-dependent iron uptake, supporting transferrin receptor activity. (The paper focuses on TfR2/HFE but uses diferric-transferrin binding/uptake assays.) Reason: Core molecular function with direct functional assay of diferric-transferrin binding and uptake. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent iron uptake |
| GO:0033572 transferrin transport | IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul... | ACCEPT | Summary: Transferrin-dependent iron uptake was directly measured, supporting transferrin transport. Reason: Core process; directly supported by transferrin-dependent iron uptake assays. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent iron uptake |
| GO:0005764 lysosome | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: A fraction of TfR1 traffics from recycling endosomes to lysosomes via a Rab12-dependent constitutive degradation pathway, and TfR1 undergoes iron-induced lysosomal degradation. Immunofluorescence localization to lysosomes is consistent with this. Reason: Reflects the receptor's degradative trafficking branch rather than its core recycling/uptake function; retained as non-core. Supporting Evidence: file:human/TFRC/TFRC-deep-research-perplexity.md Small GTPase Rab12 and its upstream activator Dennd3 regulate the trafficking of TfR1 from recycling endosomes to lysosomes, with Rab12 activation promoting TfR1 degradation |
| GO:0005768 endosome | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence localizes TfR1 to endosomes, the compartment where iron is released during the transferrin cycle. TfR1 is a canonical endosomal marker. Reason: Core localization directly supported by immunofluorescence and consistent with the receptor's endosomal iron-release/recycling cycle. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0005515 protein binding | IPI PMID:38625739 The secreted micropeptide C4orf48 enhances renal fibrosis vi... | MARK AS OVER ANNOTATED | Summary: This IPI reports an interaction between TfR1 and the secreted micropeptide C4orf48 in a renal-fibrosis context. The bare "protein binding" term is uninformative and this is a single, specialized disease-context interaction not part of TfR1's core functional repertoire. Reason: Avoid endorsing bare protein binding; a narrow disease-context interaction with no bearing on the receptor's core function and no informative molecular-function term. Supporting Evidence: PMID:38625739 The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism. |
| GO:0005886 plasma membrane | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | ACCEPT | Summary: The combined-immunodeficiency study measured TfR1 at the plasma membrane (increased steady-state surface TfR1 in patient cells with the internalization-defective variant), confirming plasma-membrane localization. Reason: Core localization directly supported; the pathogenic variant increases surface TfR1. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md Impaired TfR1 internalization (approximately fourfold lower internalization in patient T cells in the reported assays) with increased steady-state surface TfR1 |
| GO:0004998 transferrin receptor activity | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | ACCEPT | Summary: Functional studies of the TFRC variant causing combined immunodeficiency confirmed TfR1's transferrin receptor activity and its dependence on internalization for iron delivery. Reason: Defining molecular function supported by disease-variant functional analysis. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md Shows TfR1 is not only an iron receptor but a nonredundant immune-metabolic checkpoint |
| GO:0060586 multicellular organismal-level iron ion homeostasis | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | ACCEPT | Summary: Patients with the internalization-defective TFRC variant show systemic iron-handling consequences alongside immunodeficiency, supporting a role in organism-level iron homeostasis. Reason: Supported by the human disease phenotype; complements the IEA organismal iron homeostasis annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md Shows TfR1 is not only an iron receptor but a nonredundant immune-metabolic checkpoint |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5691154 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866277 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-917807 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-917814 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-917839 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-917987 | ACCEPT | Summary: TfR1 is localized to the plasma membrane as a component of the Reactome transferrin endocytosis / iron-uptake reactions. Plasma membrane is the correct location for the cell-surface receptor. Reason: Authoritative Reactome (TAS) curation of the transferrin cycle; consistent with the receptor's primary cell-surface localization. Duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005886 plasma membrane | IDA PMID:23137377 Quantitative targeted absolute proteomic analysis of transpo... | ACCEPT | Summary: Quantitative targeted proteomics of human brain microvascular endothelial cells detected TfR1 at the plasma membrane, consistent with its cell-surface localization (and BBB expression). Reason: Core surface localization corroborated by quantitative membrane proteomics. Supporting Evidence: PMID:23137377 Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model. |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | KEEP AS NON CORE | Summary: TfR1 is a leading receptor for transcytosis across the blood-brain barrier and is widely exploited to shuttle biologics into the CNS, supporting a role in transport across the blood-brain barrier. Reason: A tissue-specific manifestation of receptor-mediated transcytosis rather than the core iron-uptake function; supported by falcon deep research on RMT/BBB targeting. Supporting Evidence: PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is a leading target for **receptor-mediated transcytosis (RMT)** strategies to shuttle biologics across the BBB |
| GO:0010637 negative regulation of mitochondrial fusion | IMP PMID:26214738 Regulation of mitochondrial morphology and function by stear... | KEEP AS NON CORE | Summary: TfR1 has a signaling moonlighting function: de-stearoylated TfR1 activates JNK, leading to HUWE1-dependent mitofusin ubiquitination and reduced mitochondrial fusion (fragmentation). Stearoylation of TfR1 inhibits this, promoting fusion. TfR1 knockdown blunts fragmentation upon C18:0 removal, supporting a role in negatively regulating mitochondrial fusion via JNK signaling. Reason: A genuine, experimentally supported signaling (moonlighting) function distinct from and downstream of the core iron-uptake role; retained as non-core. Supporting Evidence: PMID:26214738 Upon loss of C18:0, TfR1 de-stearoylation activates JNK, leading to HUWE1-dependent Mfn ubiquitination |
| GO:0035556 intracellular signal transduction | IMP PMID:26214738 Regulation of mitochondrial morphology and function by stear... | KEEP AS NON CORE | Summary: TfR1 acts in an intracellular signaling pathway whereby its (de)stearoylation status controls JNK activation, linking the metabolite C18:0 to mitochondrial morphology. Reason: Supported signaling function but general and downstream of the core iron-uptake role; more specifically captured by the negative-regulation-of-mitochondrial-fusion annotation. Retained as non-core. Supporting Evidence: PMID:26214738 TfR1 induces mitochondrial fragmentation via JNK, and this is inhibited by TfR1 stearoylation |
| GO:0150104 transport across blood-brain barrier | NAS PMID:26590417 Establishment and Dysfunction of the Blood-Brain Barrier. | KEEP AS NON CORE | Summary: TfR1 mediates receptor-mediated transcytosis across the blood-brain barrier and is widely exploited to shuttle biologics into the CNS. Reason: A tissue-specific manifestation of receptor-mediated transcytosis rather than the core iron-uptake function; duplicates the accepted NAS BBB-transport annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is a leading target for **receptor-mediated transcytosis (RMT)** strategies to shuttle biologics across the BBB |
| GO:0010628 positive regulation of gene expression | IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: TfR1 depletion reduces NF-kB-dependent transcription, so TfR1 positively supports expression of NF-kB target genes by enabling IKK complex formation and NF-kB nuclear translocation. Reason: A genuine signaling/moonlighting role linking cellular iron to NF-kB-driven gene expression, distinct from and downstream of the core iron-uptake function; retained as non-core. Supporting Evidence: PMID:23016877 there is a reduction in the binding to target gene promoters and consequentially less target gene activation |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: TfR1 depletion increases apoptosis in response to TNFa, an effect rescued by raising RelA/NF-kB, indicating that TfR1 supports cell survival via NF-kB signaling. Reason: A genuine survival-signaling consequence of TfR1's NF-kB role, distinct from the core iron-uptake function; retained as non-core. Supporting Evidence: PMID:23016877 depletion of TfR1 results in an increase in apoptosis in response to TNFΞ± treatment, which is rescued by elevating the levels of RelA/NF-ΞΊB |
| GO:1900182 positive regulation of protein localization to nucleus | IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: In the absence of TfR1, NF-kB fails to translocate efficiently to the nucleus, indicating TfR1 positively regulates NF-kB nuclear localization. Reason: A specific consequence of TfR1's IKK/NF-kB signaling role, distinct from and downstream of the core iron-uptake function; retained as non-core. Supporting Evidence: PMID:23016877 in the absence of TfR1, NF-ΞΊB does not translocate to the nucleus efficiently |
| GO:0005515 protein binding | IPI PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | MODIFY | Summary: This IPI reflects TfR1 binding the IKK complex (a protein kinase complex). The bare "protein binding" term is uninformative; the specific informative function is protein kinase binding / protein-containing complex binding. Reason: Avoid endorsing bare protein binding; the interaction is with the IKK kinase complex, better captured by protein kinase binding. Proposed replacements: protein kinase binding Supporting Evidence: PMID:23016877 We have identified TfR1 (transferrin receptor 1), as a novel IKK-binding partner |
| GO:0019901 protein kinase binding | IPI PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: TfR1 binds the IKK kinase complex and is required for IKK complex formation/activity, supporting protein kinase binding. Reason: Experimentally supported interaction with the IKK kinases, but a moonlighting signaling function distinct from the core iron-uptake role; retained as non-core. Supporting Evidence: PMID:23016877 TfR1 is required for IKK complex activity, without altering IKK subunit levels |
| GO:0031334 positive regulation of protein-containing complex assembly | IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: TfR1 depletion reduces formation of the IKK complex, indicating TfR1 positively promotes assembly of this protein-containing complex. Reason: A specific moonlighting signaling function (promoting IKK complex assembly), distinct from the core iron-uptake role; retained as non-core. Supporting Evidence: PMID:23016877 it does reduce the formation of the IKK |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: TfR1 is required for IKK complex activity and TNFa-induced canonical NF-kB activation; its depletion inhibits NF-kB-dependent transcription, linking cellular iron status to canonical NF-kB signaling. Reason: A genuine, experimentally supported signaling/moonlighting function distinct from and downstream of the core iron-uptake role; retained as non-core. Supporting Evidence: PMID:23016877 these results indicate a new function for TfR1 in the control of IKK and NF-ΞΊB |
| GO:0044877 protein-containing complex binding | IPI PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N... | KEEP AS NON CORE | Summary: TfR1 was identified as a binding partner of the multi-subunit IKK complex, supporting protein-containing complex binding. Reason: Experimentally supported binding to the IKK complex, a moonlighting signaling interaction distinct from the core iron-uptake role; retained as non-core. Supporting Evidence: PMID:23016877 We have identified TfR1 (transferrin receptor 1), as a novel IKK-binding partner |
| GO:0005515 protein binding | IPI PMID:29388418 Transferrin Receptors TfR1 and TfR2 Bind Transferrin through... | MODIFY | Summary: This IPI characterizes how full-length TfR1 binds transferrin. The bare "protein binding" term is uninformative; the specific function is transferrin receptor activity. Reason: Avoid endorsing bare protein binding; the study measures ligand (transferrin) binding by the receptor, best captured by transferrin receptor activity. Proposed replacements: transferrin receptor activity Supporting Evidence: PMID:29388418 Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms |
| GO:0009986 cell surface | ISS PMID:18619525 Subcellular localization of transporters along the rat blood... | ACCEPT | Summary: In vivo biotinylation localized TfR1 to the cell surface (luminal membrane) of blood-brain barrier endothelium, consistent with its established surface localization. Reason: Cell-surface localization is the defining location of the receptor and is supported by multiple independent annotations; the ISS here adds BBB-endothelium surface evidence. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | ACCEPT | Summary: During clathrin-mediated internalization of the transferrin-TfR1 complex, TfR1 resides in the membrane of clathrin-coated endocytic vesicles. This Reactome (TAS) annotation captures a step of the iron-uptake cycle. Reason: Authoritative Reactome curation of clathrin-coated vesicle trafficking; consistent with the canonical TfR1 endocytic pathway. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-917807 | ACCEPT | Summary: As an integral membrane protein, TfR1 is present in the endosome membrane during the transferrin cycle, where iron is released at acidic pH before receptor recycling. This Reactome (TAS) annotation captures the endosomal step. Reason: Authoritative Reactome curation of the transferrin endosomal cycle; consistent with the receptor's endosomal trafficking. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-917814 | ACCEPT | Summary: As an integral membrane protein, TfR1 is present in the endosome membrane during the transferrin cycle, where iron is released at acidic pH before receptor recycling. This Reactome (TAS) annotation captures the endosomal step. Reason: Authoritative Reactome curation of the transferrin endosomal cycle; consistent with the receptor's endosomal trafficking. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-917835 | ACCEPT | Summary: As an integral membrane protein, TfR1 is present in the endosome membrane during the transferrin cycle, where iron is released at acidic pH before receptor recycling. This Reactome (TAS) annotation captures the endosomal step. Reason: Authoritative Reactome curation of the transferrin endosomal cycle; consistent with the receptor's endosomal trafficking. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0010008 endosome membrane | IDA PMID:16380373 Sec14 homology domain targets p50RhoGAP to endosomes and pro... | ACCEPT | Summary: TfR1 was used as an endosomal marker and co-localized with endosomal structures in this study, consistent with its endosome-membrane localization during the transferrin cycle. Reason: Endosome-membrane localization is a core part of the TfR1 trafficking cycle and is supported by multiple annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16380373 Sec14 homology domain targets p50RhoGAP to endosomes and pro... | ACCEPT | Summary: TfR1-positive recycling endosomes concentrate in the perinuclear endocytic recycling compartment, where TfR1 was localized in this study. Reason: The perinuclear endocytic recycling compartment is a canonical TfR1 localization; supported by direct co-localization. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0031410 cytoplasmic vesicle | IDA PMID:15229288 Over-expression of Rififylin, a new RING finger and FYVE-lik... | ACCEPT | Summary: TfR1 was tracked through cytoplasmic (recycling) vesicles in studies of the endocytic recycling compartment, consistent with its presence in cytoplasmic vesicles during the transferrin cycle. Reason: Cytoplasmic (endocytic/recycling) vesicle localization is a core part of the TfR1 trafficking cycle. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0005515 protein binding | IPI PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | MARK AS OVER ANNOTATED | Summary: This IPI from the combined-immunodeficiency study reflects TfR1 interactions; the bare "protein binding" term is uninformative. The biologically meaningful findings (receptor internalization, transferrin transport, immune proliferation) are captured by dedicated process annotations from the same paper. Reason: Avoid endorsing bare protein binding; the informative functions are annotated separately and this generic binding term adds nothing. Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. |
| GO:0030890 positive regulation of B cell proliferation | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | KEEP AS NON CORE | Summary: TfR1-mediated iron uptake is required for B-cell proliferation; the internalization-defective TFRC variant impairs B-cell proliferation in patients, contributing to combined immunodeficiency. Reason: A genuine, evidence-supported physiological consequence of the core iron-uptake function rather than a distinct molecular activity; retained as non-core. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md defective T- and B-cell proliferation, increased activation-induced apoptosis |
| GO:0042102 positive regulation of T cell proliferation | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | KEEP AS NON CORE | Summary: TfR1-mediated iron uptake is required to supply iron for lymphocyte proliferation and mitochondrial metabolism; loss-of-internalization variants impair T-cell proliferation, identifying TfR1 as a non-redundant immune-metabolic checkpoint. Reason: A genuine, evidence-supported physiological consequence of the core iron-uptake function rather than a distinct molecular activity; corroborated by falcon deep research on the iron-immunity axis, but downstream of the core receptor function. Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. file:human/TFRC/TFRC-deep-research-falcon.md TfR1 internalization is needed to supply iron for proliferation and mitochondrial metabolism |
| GO:0045830 positive regulation of isotype switching | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | KEEP AS NON CORE | Summary: Patients with the internalization-defective TFRC variant show defective immunoglobulin class-switching, a downstream immune consequence of impaired TfR1-dependent iron supply to proliferating B cells. Reason: A downstream immune phenotype secondary to the core iron-uptake function rather than a distinct molecular activity; retained as non-core. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md defective T- and B-cell proliferation, increased activation-induced apoptosis |
| GO:0031623 receptor internalization | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | ACCEPT | Summary: TfR1 internalization depends on the cytoplasmic tyrosine-based YTRF motif; pathogenic variants (e.g. p.Y20H, p.R22W) cause an internalization defect with increased steady-state surface TfR1, demonstrating the receptor's role in its own internalization. Reason: Directly supported by disease genetics (PMID:26642240) and corroborated by falcon deep research on YTRF-dependent internalization defects. Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. file:human/TFRC/TFRC-deep-research-falcon.md the cytoplasmic YTRF motif explaining trafficking-sensitive pathogenic variants |
| GO:0033572 transferrin transport | IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1... | ACCEPT | Summary: The internalization-defective TFRC variant impairs transferrin uptake/transport, consistent with TfR1's core transferrin transport function. Reason: Core process directly supported by the disease-variant functional analysis. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md increase surface TfR1, impair iron uptake, and cause combined immunodeficiency |
| GO:0005515 protein binding | IPI PMID:9990067 Association of HFE protein with transferrin receptor in cryp... | MODIFY | Summary: This IPI reflects the physical association of TfR1 with the HFE protein in crypt enterocytes. The bare "protein binding" term is uninformative; the specific complex is the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the documented HFE-TfR1 association is better captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:9990067 the HFE protein in crypt enterocytes is physically associated with the TfR and with beta2-microglobulin |
| GO:0016323 basolateral plasma membrane | IDA PMID:9990067 Association of HFE protein with transferrin receptor in cryp... | KEEP AS NON CORE | Summary: In polarized duodenal crypt enterocytes, TfR1 (with HFE) localizes to the basolateral membrane, where it takes up transferrin-bound iron from the circulation. Reason: A polarized-epithelium-specific localization of the plasma-membrane receptor; genuine but tissue-specific, retained as non-core. Supporting Evidence: PMID:9990067 The crypt cell fraction exhibited dramatically higher transferrin-bound iron uptake than villus cells |
| GO:1990712 HFE-transferrin receptor complex | IDA PMID:9990067 Association of HFE protein with transferrin receptor in cryp... | ACCEPT | Summary: TfR1 forms a stable physical complex with the HFE protein (and beta2-microglobulin) in duodenal crypt enterocytes, directly demonstrated by co-localization and co-precipitation. Reason: Direct evidence for the HFE-transferrin receptor complex in a physiological tissue. Supporting Evidence: PMID:9990067 the HFE protein in crypt enterocytes is physically associated with the TfR and with beta2-microglobulin |
| GO:0005515 protein binding | IPI PMID:18353247 HFE association with transferrin receptor 2 increases cellul... | MODIFY | Summary: This IPI relates to HFE/TfR interactions in the iron-sensing system. The bare "protein binding" term is uninformative; the relevant complex is the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the documented interaction concerns HFE, better captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:18353247 HFE and TfR2 were recently discovered to form a stable complex at the cell membrane when co-expressed in heterologous cell lines |
| GO:0005886 plasma membrane | IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul... | ACCEPT | Summary: Functional/genetic-interaction studies of HFE and the transferrin receptors place TfR1 at the plasma membrane where the iron-uptake complex forms. Reason: Consistent with the receptor's defining plasma-membrane localization; duplicates other accepted plasma-membrane annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0009897 external side of plasma membrane | IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul... | ACCEPT | Summary: The transferrin-binding ectodomain of TfR1 faces the extracellular space at the cell surface, consistent with localization to the external side of the plasma membrane. Reason: Consistent with UniProt topology and the receptor's surface ligand-binding role; duplicates other accepted external-side annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0005515 protein binding | IPI PMID:9546397 Crystal structure of the hemochromatosis protein HFE and cha... | MODIFY | Summary: This IPI reflects the structurally characterized TfR1-HFE interaction. The bare "protein binding" term is uninformative; the specific complex is the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the interaction is with HFE, best captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:9546397 HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin |
| GO:0042803 protein homodimerization activity | IPI PMID:9546397 Crystal structure of the hemochromatosis protein HFE and cha... | ACCEPT | Summary: TfR1 functions as a disulfide-linked homodimer of ~90 kDa subunits, so homodimerization is integral to its receptor architecture and ligand binding. Reason: The receptor is a well-characterized homodimer; falcon deep research describes it as a homodimeric transmembrane glycoprotein. Supporting Evidence: PMID:9546397 Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. file:human/TFRC/TFRC-deep-research-falcon.md homodimeric transmembrane glycoprotein |
| GO:1990712 HFE-transferrin receptor complex | IDA PMID:9546397 Crystal structure of the hemochromatosis protein HFE and cha... | ACCEPT | Summary: The crystal structure and binding studies demonstrate that HFE binds TfR1 at a 2:1 (TfR:HFE) stoichiometry and that HFE, transferrin, and TfR form a ternary complex. Reason: Definitive structural/biochemical evidence for the HFE-transferrin receptor complex. Supporting Evidence: PMID:9546397 TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2) |
| GO:0005515 protein binding | IPI PMID:9465039 The hemochromatosis gene product complexes with the transfer... | MODIFY | Summary: This IPI reflects the TfR1-HFE interaction. The bare "protein binding" term is uninformative; the specific complex is the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the documented interaction is with HFE, best captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:9465039 both the wild-type and H63D HFE proteins form stable complexes with the transferrin receptor (TfR) |
| GO:1990712 HFE-transferrin receptor complex | IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer... | ACCEPT | Summary: Wild-type and H63D HFE proteins form stable complexes with TfR1 in cells, directly demonstrating the HFE-transferrin receptor complex. Reason: Direct cell-based evidence for the HFE-transferrin receptor complex. Supporting Evidence: PMID:9465039 both the wild-type and H63D HFE proteins form stable complexes with the transferrin receptor (TfR) |
| GO:1903561 extracellular vesicle | HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi... | KEEP AS NON CORE | Summary: TfR1 was detected in cerebrospinal-fluid extracellular vesicles by high-throughput proteomics, consistent with its known sorting into exosomes/EVs. Reason: Genuine but secondary localization reflecting exosomal/EV sorting of TfR1; not the core membrane-receptor function. Retained as non-core. Supporting Evidence: PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset |
| GO:0071466 cellular response to xenobiotic stimulus | IDA PMID:16254249 Assigning functions to distinct regions of the N-terminus of... | REMOVE | Summary: In this study, TfR1 served as a marker of clathrin-dependent endocytosis while examining copper-stimulated internalization of the prion protein. The assignment of "cellular response to xenobiotic stimulus" to TfR1 is not supported by the paper, which concerns prion-protein endocytosis rather than a TfR1 xenobiotic response. Reason: The cited paper uses TfR1 only as an endocytic control/marker and provides no evidence that TfR1 mediates a cellular response to a xenobiotic; this is an erroneous over-annotation. Supporting Evidence: PMID:16254249 its copper-stimulated, clathrin-dependent endocytosis |
| GO:0055037 recycling endosome | IDA PMID:24561039 Rab11 endosomes contribute to mitotic spindle organization a... | ACCEPT | Summary: TfR1 is the canonical marker of Rab11-positive recycling endosomes and was used as such in this study, consistent with its recycling-endosome localization. Reason: Recycling-endosome localization is core to the TfR1 transferrin cycle and is supported by multiple annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0055037 recycling endosome | IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: TfR1 was used as a recycling-endosome marker in this autophagy study, consistent with its established recycling-endosome localization. Reason: Recycling-endosome localization is core to the TfR1 transferrin cycle; supported by multiple annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0001558 regulation of cell growth | IMP NOT PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human... | ACCEPT | Summary: This NOT annotation derives from a study primarily on the GPI-anchored transferrin homolog p97/melanotransferrin, using TfR-deficient CHO cells transfected with human TfR. The negated regulation-of-cell-growth annotation indicates TfR1 was not shown to regulate cell growth in this system. Reason: A NOT annotation reflecting absence of a cell-growth-regulation role for TfR1 in this experimental context; consistent with TfR1 being an iron-uptake receptor rather than a direct growth regulator. Retained as a documented negative annotation. Supporting Evidence: PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human p97 |
| GO:0006826 iron ion transport | IDA PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human... | ACCEPT | Summary: In this study, transferrin-receptor-mediated iron uptake served as the canonical comparator to the novel p97/melanotransferrin pathway, consistent with TfR1's core iron-transport function. Reason: Iron ion transport is the receptor's core process; here TfR-mediated iron uptake was directly assayed in transfected cells. Duplicates the accepted IBA iron ion transport annotation. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0009986 cell surface | IDA PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human... | ACCEPT | Summary: TfR was expressed at the cell surface of transfected CHO cells in this iron-uptake study, consistent with its established surface localization. Reason: Cell-surface localization is the defining location of the receptor; duplicates other accepted cell-surface annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md TfR1 is the major cell-surface receptor that mediates cellular iron import by binding diferric transferrin |
| GO:0042127 regulation of cell population proliferation | IMP NOT PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human... | ACCEPT | Summary: This NOT annotation derives from the p97/melanotransferrin iron-uptake study using TfR-transfected CHO cells, indicating TfR1 was not shown to regulate cell proliferation in this experimental system. Reason: A NOT annotation documenting absence of a direct proliferation-regulation role for TfR1 in this context; consistent with TfR1 functioning as an iron-uptake receptor. Retained as a documented negative annotation. Supporting Evidence: PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human p97 |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: TfR1 was flagged as a putative mRNA-binding protein in a proteome-wide UV-crosslinking "interactome capture" screen. TfR1 is a type II transmembrane iron-uptake receptor with no known sequence-specific RNA-binding domain, so this is most plausibly an incidental high-throughput hit. Reason: High-throughput RBP-atlas hit lacking corroborating mechanistic evidence or an RNA-binding domain; likely a screening artifact and not a core function. Supporting Evidence: PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins |
| GO:0072562 blood microparticle | HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d... | KEEP AS NON CORE | Summary: TfR1 was detected by proteomics in plasma microvesicles/microparticles, consistent with its shedding into circulating vesicles (and as the soluble sTfR). Reason: Secondary localization reflecting vesicular/soluble release of TfR1 into blood; not the core membrane-receptor function. Retained as non-core. Supporting Evidence: PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy donors reveals high individual variability |
| GO:0005615 extracellular space | HDA PMID:22664934 Comparison of tear protein levels in breast cancer patients ... | KEEP AS NON CORE | Summary: TfR1 was detected in tear-fluid proteomics, consistent with the presence of the shed soluble receptor (sTfR) in extracellular/body fluids. Reason: Reflects the shed soluble ectodomain in extracellular fluid rather than the core membrane-receptor function; retained as non-core. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. |
| GO:0003725 double-stranded RNA binding | IDA PMID:21266579 Raftlin is involved in the nucleocapture complex to induce p... | MARK AS OVER ANNOTATED | Summary: This annotation derives from a study of poly(I:C) (dsRNA mimic) uptake, where TfR1 was implicated in the "nucleocapture" complex that internalizes extracellular dsRNA for TLR3 activation. Any dsRNA association is in the context of receptor-mediated uptake rather than a sequence-specific dsRNA-binding molecular function. Reason: TfR1 lacks a recognized dsRNA-binding domain; its reported involvement is in receptor-mediated uptake of extracellular nucleic acids, so the bare dsRNA-binding MF term over-interprets the data. Supporting Evidence: PMID:21266579 Raftlin is involved in the nucleocapture complex to induce poly(I:C)-mediated TLR3 activation |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: TfR1 was detected by proteomics in B-cell exosomes, consistent with its well-documented sorting into exosomes (a hallmark of reticulocyte maturation). Reason: Secondary localization reflecting exosomal sorting of TfR1; not the core membrane-receptor function. Retained as non-core. Supporting Evidence: PMID:20458337 MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis |
| GO:0005515 protein binding | IPI PMID:10638746 Crystal structure of the hereditary haemochromatosis protein... | MODIFY | Summary: This IPI reflects the co-crystal structure of HFE complexed with TfR1. The bare "protein binding" term is uninformative; the specific complex is the HFE-transferrin receptor complex. Reason: Avoid endorsing bare protein binding; the structurally resolved interaction is with HFE, best captured by the HFE-transferrin receptor complex term. Proposed replacements: HFE-transferrin receptor complex Supporting Evidence: PMID:10638746 Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:20202662 Ebola virus uses clathrin-mediated endocytosis as an entry p... | ACCEPT | Summary: TfR1 was used as a marker of the perinuclear endocytic recycling compartment in this Ebola entry study, consistent with its established perinuclear recycling-endosome localization. Reason: The perinuclear endocytic recycling compartment is a canonical TfR1 localization; supported by multiple annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md internalizes via clathrin/AP-2-mediated endocytosis, releases iron in acidic endosomes, and recycles apo-transferrin/TfR1 to the surface |
| GO:0005905 clathrin-coated pit | IDA PMID:12857860 Myo6 facilitates the translocation of endocytic vesicles fro... | ACCEPT | Summary: TfR1 was localized to clathrin-coated pits / newly uncoated endocytic vesicles in this Myo6 study, consistent with its concentration in coated pits as endocytic cargo. Reason: Clathrin-coated-pit localization is the entry point of the TfR1 endocytic cycle; supported by multiple annotations. Supporting Evidence: PMID:12857860 myo6 was associated with peripherally located vesicles that contained the transferrin receptor |
| GO:0005768 endosome | IDA PMID:14612438 Zn2+-stimulated endocytosis of the mZIP4 zinc transporter re... | ACCEPT | Summary: TfR1 was used as an endosomal marker in this ZIP4 endocytosis study, consistent with its endosomal localization during the transferrin cycle. Reason: Endosomal localization is core to the TfR1 trafficking cycle; supported by multiple annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0004998 transferrin receptor activity | TAS PMID:10192390 Transferrin receptor is necessary for development of erythro... | ACCEPT | Summary: TfR1-knockout mice die in utero with severe anemia and neurological defects, demonstrating that the receptor's transferrin-binding/iron-delivery activity is essential. The transferrin cycle is the general mechanism for cellular iron uptake. Reason: Defining molecular function with strong in vivo genetic support; duplicates accepted transferrin receptor activity annotations. Supporting Evidence: PMID:10192390 Diferric Trf interacts with cell-surface Trf receptor (Trfr) to undergo receptor-mediated endocytosis into specialized endosomes |
| GO:0005768 endosome | TAS PMID:8394993 Differential effects of antimycin A on endocytosis and exocy... | ACCEPT | Summary: Transferrin endocytosis traffics TfR1 through endosomal compartments, as studied here via transferrin internalization/externalization, consistent with TfR1's endosomal localization. Reason: Endosomal localization is core to the TfR1 transferrin cycle; supported by multiple annotations. Supporting Evidence: file:human/TFRC/TFRC-deep-research-falcon.md acidic endosomes (pH β€ 5.5) |
| GO:0005886 plasma membrane | TAS PMID:6090955 Primary structure of human transferrin receptor deduced from... | ACCEPT | Summary: The original cloning/primary-structure paper established TfR1 as a type II transmembrane plasma-membrane glycoprotein. Reason: Foundational characterization of the receptor's plasma-membrane localization; duplicates other accepted plasma-membrane annotations. Supporting Evidence: PMID:6090955 Primary structure of human transferrin receptor deduced from the mRNA sequence |
| GO:0006879 intracellular iron ion homeostasis | TAS PMID:10192390 Transferrin receptor is necessary for development of erythro... | ACCEPT | Summary: By controlling the rate of transferrin-bound iron import, TfR1 is central to cellular iron homeostasis; its loss in mice causes severe anemia, underscoring this role. Reason: Core process supported by in vivo genetics; duplicates accepted intracellular iron homeostasis annotations. Supporting Evidence: PMID:10192390 Transferrin receptor is necessary for development of erythrocytes and the nervous system |
| GO:0004998 transferrin receptor activity | NAS PMID:1871153 Characterization of transferrin receptor released by K562 er... | ACCEPT | Summary: This study characterized the released (soluble) transferrin receptor, attributing transferrin-binding (receptor) activity to TfR1. Reason: Defining molecular function; duplicates accepted transferrin receptor activity annotations. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. |
| GO:0005576 extracellular region | IDA PMID:1871153 Characterization of transferrin receptor released by K562 er... | KEEP AS NON CORE | Summary: A proteolytically cleaved/shed soluble form of the transferrin receptor (sTfR) circulates in the extracellular compartment and serves as a clinical biomarker of iron demand and erythropoiesis. Reason: Reflects the shed soluble ectodomain rather than the membrane receptor's core function; supported by falcon deep research describing sTfR generation by proteolytic shedding. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. file:human/TFRC/TFRC-deep-research-falcon.md generated by **proteolytic cleavage/shedding** of membrane TfR; it rises in **iron deficiency** and with **expanded erythropoiesis** |
| GO:0006879 intracellular iron ion homeostasis | NAS PMID:1871153 Characterization of transferrin receptor released by K562 er... | ACCEPT | Summary: The soluble transferrin receptor (sTfR) reflects cellular iron demand, linking TfR1 to intracellular iron homeostasis. Reason: Core process; duplicates accepted intracellular iron homeostasis annotations. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. |
| GO:0016020 membrane | NAS PMID:1871153 Characterization of transferrin receptor released by K562 er... | MARK AS OVER ANNOTATED | Summary: TfR1 is an integral membrane protein; "membrane" is a correct but very general location subsumed by the more specific plasma-membrane annotations. Reason: Uninformatively broad cellular-component term; more specific membrane locations are annotated. Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells. |
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Download this section (compressed HTML)Q: Should TfR1's role as a receptor for H-chain ferritin (and uptake of ferritin-bound iron) be captured by a dedicated molecular-function term distinct from transferrin receptor activity?
Suggested experts: Li L, Seaman WE
Q: Are TfR1's reported signaling/moonlighting functions (JNK regulation via stearoylation; IKK-NF-kB signaling) sufficiently established to be considered part of its core annotation, or should they remain non-core?
Suggested experts: Senyilmaz D, Teleman AA, Rocha S
Experiment: Compare proliferation, isotype switching, and mitochondrial respiration in primary lymphocytes carrying the internalization-defective TFRC variant versus wild-type, with and without iron supplementation/bypass, to separate iron-supply from signaling effects.
Hypothesis: TfR1-mediated iron supply, rather than a direct signaling function, accounts for the lymphocyte-proliferation and class-switching defects in TFRC-deficiency.
Type: functional rescue and immunometabolic assay
Experiment: Use stearoylation-deficient TfR1 mutants (and ZDHHC6 manipulation) in cells with iron uptake held constant to test whether JNK activation and mitochondrial fragmentation can be uncoupled from transferrin-iron import.
Hypothesis: TfR1 stearoylation status controls mitochondrial morphology via JNK independently of its iron-uptake activity.
Type: structure-function and live-cell imaging assay
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