TFR2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004998 transferrin receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: TFR2 directly binds transferrin and functions as a lower-affinity second transferrin receptor. Reason: Cell-surface binding/uptake experiments and full-length receptor biochemistry directly support transferrin receptor activity. The IBA, IEA, IDA, and NAS instances converge on the same specific molecular function. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:10409623 marked increase in Tf-bound (55)Fe uptake.
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: The extracellular receptor domain of membrane TFR2-alpha is active at the external face of the plasma membrane. Reason: TFR2-alpha is a type-II single-pass cell-surface receptor, and its extracellular domain binds transferrin and HFE/HJV partners. Phylogenetic, electronic, and experimental instances are consistent with this topology. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane PMID:22728873 required for the binding of both HFE and HJV.
GO:0140298 endocytic iron import into cell	IBA GO_REF:0000033	ACCEPT	Summary: TFR2 binds and internalizes transferrin-bound iron, including enhanced uptake when HFE is co-expressed. Reason: The original human TFR2-alpha transfection study demonstrated transferrin-bound iron uptake, and the HFE co-expression study increased transferrin-dependent uptake. Although iron sensing is the dominant systemic role, endocytic iron import is a genuine receptor activity. Supporting Evidence: PMID:10409623 marked increase in Tf-bound (55)Fe uptake. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0004998 transferrin receptor activity	IEA GO_REF:0000120	ACCEPT	Summary: TFR2 directly binds transferrin and functions as a lower-affinity second transferrin receptor. Reason: Cell-surface binding/uptake experiments and full-length receptor biochemistry directly support transferrin receptor activity. The IBA, IEA, IDA, and NAS instances converge on the same specific molecular function. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:10409623 marked increase in Tf-bound (55)Fe uptake.
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Cytoplasmic localization is assigned from the reviewed record for the transmembrane-domain-lacking beta isoform. Reason: The location is plausible and explicitly tied to isoform Beta, but the GOA row is not isoform-qualified and cytoplasmic TFR2 is not the site of the alpha isoform's principal receptor and iron-sensing functions. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt [Isoform Beta]: Cytoplasm PMID:10409623 protein including the putative transmembrane domain.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: TFR2-alpha is a single-pass cell-surface receptor that operates at the plasma membrane. Reason: Reviewed UniProt topology, the original cloning/localization evidence, HFE/HJV complex experiments, and the Reactome holo-transferrin-binding event consistently place functional TFR2-alpha at the plasma membrane. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane
GO:0006898 receptor-mediated endocytosis	IEA GO_REF:0000117	ACCEPT	Summary: TFR2-mediated uptake of transferrin-bound iron proceeds by receptor-mediated endocytosis. Reason: The original uptake experiment and HFE-dependent enhancement establish receptor-dependent internalization. This process is supported even though systemic sensing, rather than bulk iron uptake, is TFR2's dominant physiological role. Supporting Evidence: PMID:10409623 marked increase in Tf-bound (55)Fe uptake. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0009897 external side of plasma membrane	IEA GO_REF:0000117	ACCEPT	Summary: The extracellular receptor domain of membrane TFR2-alpha is active at the external face of the plasma membrane. Reason: TFR2-alpha is a type-II single-pass cell-surface receptor, and its extracellular domain binds transferrin and HFE/HJV partners. Phylogenetic, electronic, and experimental instances are consistent with this topology. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane PMID:22728873 required for the binding of both HFE and HJV.
GO:0033572 transferrin transport	IEA GO_REF:0000120	ACCEPT	Summary: TFR2 binds circulating transferrin and transports the ligand through an endocytic receptor pathway. Reason: Specific transferrin binding and transferrin-dependent uptake support transport of the ligand; automated and experimental instances agree with direct biochemical evidence. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0060586 multicellular organismal-level iron ion homeostasis	IEA GO_REF:0000117	ACCEPT	Summary: TFR2 is required for the hepcidin response that maintains systemic iron balance. Reason: Loss of TFR2 causes hereditary iron overload, and patients with TFR2 hemochromatosis lack the acute hepcidin response to oral iron. Hepatocyte-targeted animal rescue independently supports an organism-level homeostatic role. Supporting Evidence: PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. PMID:20177050 Expression of Tfr2 in Tfr2-deficient mice had a similar effect
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: The HuRI source reports binary TFR2 interactions with OLFM4 and SEC22A, but the generic term does not identify an informative molecular activity. Reason: Generic protein binding is uninformative, and the cached main paper does not establish a TFR2-specific physiological consequence for either high-throughput interaction. The source interactions can remain provenance, but should not define TFR2 function. Supporting Evidence: file:human/TFR2/TFR2-deep-research-manual.md TFR2 is a hepatocyte transferrin-saturation sensor required for an appropriate hepcidin
GO:1990712 HFE-transferrin receptor complex	IEA GO_REF:0000107	ACCEPT	Summary: TFR2 forms an HFE-containing membrane complex that participates in transferrin sensing and hepcidin regulation. Reason: Cell localization/co-expression studies and direct co-immunoprecipitation support an HFE-TFR2 complex. HJV joins the complex and provides a biochemical link to BMP-SMAD hepcidin control. Supporting Evidence: PMID:22728873 that HFE, TfR2, and HJV form a multi-protein membrane complex. PMID:20177050 formation of the Hfe/Tfr2 complex that regulates hepcidin expression.
GO:0033572 transferrin transport	IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2 binds circulating transferrin and transports the ligand through an endocytic receptor pathway. Reason: Specific transferrin binding and transferrin-dependent uptake support transport of the ligand; automated and experimental instances agree with direct biochemical evidence. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0006879 intracellular iron ion homeostasis	IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2 couples transferrin-bound iron status to uptake and hepcidin-dependent regulation of body iron distribution. Reason: HFE-dependent changes in TFR2 transferrin affinity and uptake, transferrin-dependent stabilization of TFR2, and the hemochromatosis phenotype consistently support iron homeostasis. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis.
GO:0060586 multicellular organismal-level iron ion homeostasis	IMP PMID:21173098 A time course of hepcidin response to iron challenge in pati...	ACCEPT	Summary: TFR2 is required for the hepcidin response that maintains systemic iron balance. Reason: Loss of TFR2 causes hereditary iron overload, and patients with TFR2 hemochromatosis lack the acute hepcidin response to oral iron. Hepatocyte-targeted animal rescue independently supports an organism-level homeostatic role. Supporting Evidence: PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. PMID:20177050 Expression of Tfr2 in Tfr2-deficient mice had a similar effect
GO:0005515 protein binding	IPI PMID:29388418 Transferrin Receptors TfR1 and TfR2 Bind Transferrin through...	MARK AS OVER ANNOTATED	Summary: This interaction is TFR2 binding to its ligand transferrin, already represented by transferrin receptor activity. Reason: The interaction is direct and biologically central, but generic protein binding discards ligand and receptor specificity. GO:0004998 captures the supported molecular function, so the generic parent is over-annotation. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf.
GO:0140298 endocytic iron import into cell	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2 binds and internalizes transferrin-bound iron, including enhanced uptake when HFE is co-expressed. Reason: The original human TFR2-alpha transfection study demonstrated transferrin-bound iron uptake, and the HFE co-expression study increased transferrin-dependent uptake. Although iron sensing is the dominant systemic role, endocytic iron import is a genuine receptor activity. Supporting Evidence: PMID:10409623 marked increase in Tf-bound (55)Fe uptake. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5691150	ACCEPT	Summary: TFR2-alpha is a single-pass cell-surface receptor that operates at the plasma membrane. Reason: Reviewed UniProt topology, the original cloning/localization evidence, HFE/HJV complex experiments, and the Reactome holo-transferrin-binding event consistently place functional TFR2-alpha at the plasma membrane. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane Reactome:R-HSA-5691150 Two holoTFs bind to a TFR2 dimer
GO:0010039 response to iron ion	IMP PMID:21173098 A time course of hepcidin response to iron challenge in pati...	ACCEPT	Summary: Human TFR2 is required for the acute hepcidin response to an oral iron challenge. Reason: The cited patient study directly measured the iron challenge response and found it absent in TFR2 hemochromatosis, supporting a response-to-iron process. Supporting Evidence: PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis.
GO:0090277 positive regulation of peptide hormone secretion	IMP PMID:21173098 A time course of hepcidin response to iron challenge in pati...	ACCEPT	Summary: TFR2 positively supports the iron-induced rise in circulating hepcidin, a liver-secreted peptide hormone. Reason: The human challenge study measured serum hepcidin and found the response absent in TFR2 hemochromatosis. Together with hepatocyte rescue and expression data, this supports positive regulation of hepcidin secretion at the available GO term granularity. Supporting Evidence: PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. PMID:20576915 Hepcidin expression was increased in primary human hepatocytes following 24-h
GO:0031410 cytoplasmic vesicle	IDA PMID:12704209 Co-localization of the mammalian hemochromatosis gene produc...	ACCEPT	Summary: TFR2 and HFE co-localize in a specialized intracellular vesicular compartment in intestinal cells. Reason: Confocal localization in human Caco-2 cells and intestinal crypts directly supports a cytoplasmic vesicle pool relevant to transferrin-iron trafficking. Supporting Evidence: PMID:12704209 co-localized to a distinct CD63-negative vesicular compartment showing marked
GO:1990712 HFE-transferrin receptor complex	IDA PMID:12704209 Co-localization of the mammalian hemochromatosis gene produc...	ACCEPT	Summary: TFR2 forms an HFE-containing membrane complex that participates in transferrin sensing and hepcidin regulation. Reason: Cell localization/co-expression studies and direct co-immunoprecipitation support an HFE-TFR2 complex. HJV joins the complex and provides a biochemical link to BMP-SMAD hepcidin control. Supporting Evidence: PMID:22728873 that HFE, TfR2, and HJV form a multi-protein membrane complex. PMID:20177050 formation of the Hfe/Tfr2 complex that regulates hepcidin expression.
GO:0004998 transferrin receptor activity	IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2 directly binds transferrin and functions as a lower-affinity second transferrin receptor. Reason: Cell-surface binding/uptake experiments and full-length receptor biochemistry directly support transferrin receptor activity. The IBA, IEA, IDA, and NAS instances converge on the same specific molecular function. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:10409623 marked increase in Tf-bound (55)Fe uptake.
GO:0005515 protein binding	IPI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	MARK AS OVER ANNOTATED	Summary: This interaction is transferrin binding in an HFE-dependent uptake assay, already represented by transferrin receptor activity. Reason: The experiment is valid, but generic protein binding is less informative than the existing transferrin receptor activity and HFE-transferrin receptor complex annotations. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0005886 plasma membrane	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2-alpha is a single-pass cell-surface receptor that operates at the plasma membrane. Reason: Reviewed UniProt topology, the original cloning/localization evidence, HFE/HJV complex experiments, and the Reactome holo-transferrin-binding event consistently place functional TFR2-alpha at the plasma membrane. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane
GO:0006898 receptor-mediated endocytosis	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2-mediated uptake of transferrin-bound iron proceeds by receptor-mediated endocytosis. Reason: The original uptake experiment and HFE-dependent enhancement establish receptor-dependent internalization. This process is supported even though systemic sensing, rather than bulk iron uptake, is TFR2's dominant physiological role. Supporting Evidence: PMID:10409623 marked increase in Tf-bound (55)Fe uptake. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0009897 external side of plasma membrane	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: The extracellular receptor domain of membrane TFR2-alpha is active at the external face of the plasma membrane. Reason: TFR2-alpha is a type-II single-pass cell-surface receptor, and its extracellular domain binds transferrin and HFE/HJV partners. Phylogenetic, electronic, and experimental instances are consistent with this topology. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane PMID:22728873 required for the binding of both HFE and HJV.
GO:0033572 transferrin transport	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2 binds circulating transferrin and transports the ligand through an endocytic receptor pathway. Reason: Specific transferrin binding and transferrin-dependent uptake support transport of the ligand; automated and experimental instances agree with direct biochemical evidence. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0045807 positive regulation of endocytosis	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: HFE association increases the TFR2-dependent uptake of transferrin-bound iron. Reason: The cited co-expression experiment reports increased transferrin-dependent uptake, supporting positive regulation of the endocytic receptor process in the tested system. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent
GO:0071281 cellular response to iron ion	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	ACCEPT	Summary: TFR2 responds to transferrin-bound iron and is required to couple iron status to hepcidin output. Reason: Cell-based uptake/stabilization evidence and the absent patient hepcidin response to iron establish a bona fide cellular response to iron. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis.
GO:1903319 positive regulation of protein maturation	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	KEEP AS NON CORE	Summary: TFR2 co-expression accelerates HFE biosynthesis and late-Golgi maturation in a heterologous cell system. Reason: The cited experiment directly supports positive regulation of HFE maturation, but this partner-specific trafficking effect is secondary to TFR2's core transferrin-sensing and iron-homeostasis functions. Supporting Evidence: PMID:18353247 accelerated HFE biosynthesis and late-Golgi maturation
GO:0045944 positive regulation of transcription by RNA polymerase II	IGI PMID:25635054 CD81 promotes both the degradation of transferrin receptor 2...	ACCEPT	Summary: TFR2, together with CD81, is required to maintain hepcidin expression downstream of iron sensing. Reason: CD81 knockdown in TFR2-expressing hepatoma cells decreased hepcidin expression, and independent human hepatocyte data link TFR2 abundance to iron-induced hepcidin mRNA. This supports a positive role upstream of RNA polymerase II transcription rather than DNA binding by TFR2 itself. Supporting Evidence: PMID:25635054 TfR2/CD81 complex is involved in the maintenance of hepcidin mRNA. PMID:20576915 Hepcidin expression was positively
GO:0005515 protein binding	IPI PMID:25635054 CD81 promotes both the degradation of transferrin receptor 2...	MARK AS OVER ANNOTATED	Summary: CD81 directly interacts with TFR2 and regulates its turnover and maintenance of hepcidin expression. Reason: The physical interaction is real, but protein binding does not encode the regulatory consequence or partner specificity and should not be retained as a defining function. Supporting Evidence: PMID:25635054 TfR2/CD81 complex is involved in the maintenance of hepcidin mRNA.
GO:0005515 protein binding	IPI PMID:22728873 The hemochromatosis proteins HFE, TfR2, and HJV form a membr...	MARK AS OVER ANNOTATED	Summary: TFR2 physically associates with HFE in the membrane iron-sensing complex. Reason: The interaction is well supported, but generic protein binding is redundant with the specific HFE-transferrin receptor complex annotation and is not informative as a molecular function. Supporting Evidence: PMID:22728873 that HFE, TfR2, and HJV form a multi-protein membrane complex.
GO:0039706 co-receptor binding	IPI PMID:22728873 The hemochromatosis proteins HFE, TfR2, and HJV form a membr...	ACCEPT	Summary: The TFR2 extracellular domain directly binds the BMP co-receptor HJV and its homolog RGMA. Reason: Co-immunoprecipitation and domain mapping identify TFR2 residues 120-139 as necessary for binding HJV/RGMA, making co-receptor binding an informative molecular activity. Supporting Evidence: PMID:22728873 required for the binding of both HFE and HJV. PMID:22728873 that HFE, TfR2, and HJV form a multi-protein membrane complex.
GO:1990712 HFE-transferrin receptor complex	IDA PMID:22728873 The hemochromatosis proteins HFE, TfR2, and HJV form a membr...	ACCEPT	Summary: TFR2 forms an HFE-containing membrane complex that participates in transferrin sensing and hepcidin regulation. Reason: Cell localization/co-expression studies and direct co-immunoprecipitation support an HFE-TFR2 complex. HJV joins the complex and provides a biochemical link to BMP-SMAD hepcidin control. Supporting Evidence: PMID:22728873 that HFE, TfR2, and HJV form a multi-protein membrane complex. PMID:20177050 formation of the Hfe/Tfr2 complex that regulates hepcidin expression.
GO:0006879 intracellular iron ion homeostasis	TAS PMID:15319276 Regulation of transferrin receptor 2 protein levels by trans...	ACCEPT	Summary: TFR2 couples transferrin-bound iron status to uptake and hepcidin-dependent regulation of body iron distribution. Reason: HFE-dependent changes in TFR2 transferrin affinity and uptake, transferrin-dependent stabilization of TFR2, and the hemochromatosis phenotype consistently support iron homeostasis. Supporting Evidence: PMID:18353247 increased affinity for diferric transferrin, increased transferrin-dependent PMID:21173098 iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis.
GO:0004998 transferrin receptor activity	NAS PMID:10409623 Molecular cloning of transferrin receptor 2. A new member of...	ACCEPT	Summary: TFR2 directly binds transferrin and functions as a lower-affinity second transferrin receptor. Reason: Cell-surface binding/uptake experiments and full-length receptor biochemistry directly support transferrin receptor activity. The IBA, IEA, IDA, and NAS instances converge on the same specific molecular function. Supporting Evidence: PMID:29388418 TfR1 and TfR2 have distinct mechanisms for stabilizing a complex with holo-Tf. PMID:10409623 marked increase in Tf-bound (55)Fe uptake.
GO:0005886 plasma membrane	NAS PMID:10409623 Molecular cloning of transferrin receptor 2. A new member of...	ACCEPT	Summary: TFR2-alpha is a single-pass cell-surface receptor that operates at the plasma membrane. Reason: Reviewed UniProt topology, the original cloning/localization evidence, HFE/HJV complex experiments, and the Reactome holo-transferrin-binding event consistently place functional TFR2-alpha at the plasma membrane. Supporting Evidence: file:human/TFR2/TFR2-uniprot.txt Cell membrane; Single-pass type II membrane
GO:0006826 iron ion transport	NAS PMID:10409623 Molecular cloning of transferrin receptor 2. A new member of...	ACCEPT	Summary: TFR2-alpha mediates cellular uptake of transferrin-bound iron. Reason: The original transfection experiment directly showed increased uptake of transferrin-bound radiolabeled iron. The broad transport term is valid even though endocytic iron import is more precise. Supporting Evidence: PMID:10409623 marked increase in Tf-bound (55)Fe uptake.

Gene Description

Existing Annotations Review

Core Functions

Cell-surface TFR2-alpha homodimers bind transferrin and mediate receptor-dependent endocytosis and cellular uptake of transferrin-bound iron.

In hepatocytes, transferrin-bound TFR2-alpha participates in an HFE/HJV-associated plasma-membrane iron-sensing complex that promotes the hepcidin response and maintains systemic iron homeostasis.

References

Suggested Questions for Experts

Suggested Experiments

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Manual

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Notes

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