Affinage

TFR2

Transferrin receptor protein 2 · UniProt Q9UP52

Length
801 aa
Mass
88.8 kDa
Annotated
2026-06-10
68 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFR2 is a hepatic iron sensor that couples circulating diferric (holo)transferrin levels to transcription of the iron-regulatory hormone hepcidin, and its loss-of-function causes type 3 hereditary hemochromatosis with systemic iron overload (PMID:10802645). Genetic studies place TFR2 upstream of hepcidin specifically in the iron-dependent — not inflammatory — branch of regulation: TFR2-mutant mice and patients fail to raise hepcidin in response to iron loading, while IL-6/LPS induction is preserved (PMID:15345587, PMID:15486069, PMID:21173098). TFR2 binds holotransferrin through a binding mode distinct from TFR1, with the helical domain and apical-arm-junction residues governing transferrin engagement (PMID:29388418). At the hepatocyte surface TFR2 assembles into a multi-protein membrane complex with HFE and the BMP co-receptor HJV; residues 120–139 of its extracellular domain are required for binding both partners, and HFE and TFR2 act in the same regulatory pathway, each being limiting and non-redundant for full hepcidin control (PMID:20177050, PMID:22728873, PMID:24284962). Functionally, TFR2 is required for iron-dependent upregulation of Bmp6 and downstream SMAD1/5/9 phosphorylation that drives hepcidin transcription, and is necessary for acute iron-dependent hepcidin induction independent of its dispensable role in transferrin-iron uptake (PMID:24284962, PMID:41662592). TFR2 localizes to lipid rafts where holotransferrin binding activates ERK1/2 and p38 MAPK signaling, and its stability is controlled by CD81, whose own turnover is set by the GRAIL E3 ligase, with the TFR2/CD81 complex maintaining hepcidin expression independently of BMP signaling (PMID:17046995, PMID:25635054). Beyond the liver, an erythroid pool of TFR2 partners with and stabilizes the erythropoietin receptor to tune erythropoiesis to iron availability, and a distinct beta isoform controls splenic iron efflux via ferroportin (PMID:20179178, PMID:24847265). TFR2 abundance is further set transcriptionally by SP1 and by EZH2-mediated H3K27me3 repression, and by RAB12-dependent lysosomal degradation downstream of DENND3 (PMID:25635054, PMID:27013087, PMID:36729283, PMID:38623968).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Established that TFR2 is essential for systemic iron homeostasis by linking its loss to a Mendelian iron-overload disease.

    Evidence Genetic mapping and identification of a homozygous nonsense mutation in hemochromatosis families

    PMID:10802645

    Open questions at the time
    • Did not define the molecular function of TFR2
    • No mechanism connecting TFR2 loss to iron accumulation
  2. 2004 High

    Placed TFR2 upstream of hepcidin and showed it is required for iron-dependent but not inflammatory hepcidin regulation, defining its signaling branch.

    Evidence Northern blot of hepcidin/DMT1 in TfR2(Y245X) mice, iron loading, and IL-6/LPS stimulation of mutant hepatocytes; urinary hepcidin in TFR2-mutant patients

    PMID:15345587 PMID:15486069

    Open questions at the time
    • Did not identify the upstream sensing event or molecular partners
    • Did not resolve how the iron signal is transmitted to the hepcidin promoter
  3. 2006 High

    Clarified that TFR2 acts in parallel to, not within, the core BMP-driven hepcidin transcription machinery.

    Evidence BMP2/4/9 stimulation of primary hepatocytes from Tfr2-mutant vs wild-type mice; lipid raft fractionation, co-IP with caveolin-1/CD81, and MAPK assays

    PMID:16801541 PMID:17046995

    Open questions at the time
    • Functional consequence of raft-dependent ERK/p38 activation for hepcidin not fully resolved
    • Relationship between MAPK signaling and BMP-SMAD output unclear
  4. 2010 High

    Demonstrated by genetic rescue and isoform-specific knockouts that HFE and TFR2 act non-redundantly in one hepcidin-regulatory complex, and separated hepatic from extrahepatic TFR2 functions.

    Evidence Hepatocyte-specific AAV cross-complementation of Hfe/Tfr2 knockouts; comparison of Tfr2 KO, beta-Tfr2 KI, and liver-specific conditional knockout mice; human acute oral iron challenge

    PMID:20177050 PMID:20179178 PMID:21173098

    Open questions at the time
    • Molecular nature of the HFE/TFR2 interaction not directly resolved
    • Mechanism of beta-isoform control of splenic ferroportin unknown
  5. 2012 High

    Defined the physical architecture of the surface sensing complex by mapping TFR2 extracellular residues required for HFE and HJV binding, but a competing study questioned a direct HFE-TFR2 interaction.

    Evidence Glycerol gradient sedimentation, reciprocal co-IP, and domain mapping in HuH7 cells; proximity ligation assay in a stable co-expression system

    PMID:22728873 PMID:24155934

    Open questions at the time
    • Direct vs indirect (HJV-bridged) HFE-TFR2 association unresolved between Co-IP and PLA methods
    • Stoichiometry and ligand-dependence of complex assembly not defined
  6. 2013 High

    Resolved that TFR2 and HFE perform distinct cell-compartment-specific roles in iron sensing — TFR2 enabling hepatocyte-iron-driven Bmp6 induction — and extended TFR2 function to erythroid EPOR stabilization.

    Evidence Four-genotype mouse comparison with dietary vs parenteral iron loading and SMAD analysis; review synthesis of Tfr2-null erythroid and double-knockout data

    PMID:24284962 PMID:24847265

    Open questions at the time
    • Molecular basis of TFR2-EPOR stabilization not directly shown in primary data here
    • How hepatocyte iron is sensed to drive Bmp6 remains undefined
  7. 2015 High

    Identified post-translational control of TFR2 stability through a CD81/GRAIL axis that maintains hepcidin expression independently of BMP signaling.

    Evidence Yeast two-hybrid with TFR2 cytoplasmic domain, co-precipitation, CD81/GRAIL knockdown, hepcidin mRNA and ERK1/2 assays

    PMID:25635054

    Open questions at the time
    • How CD81-mediated TFR2 turnover integrates with ligand sensing not defined
    • GRAIL substrate specificity in vivo not established
  8. 2016 Medium

    Established transcriptional control of TFR2 by SP1 as an upstream node of the TFR2/hepcidin axis with therapeutic relevance.

    Evidence Sp1 manipulation with qRT-PCR/immunoblot and adenoviral forced Tfr2 expression in Fah(-/-) mice

    PMID:27013087

    Open questions at the time
    • Single lab; direct SP1 promoter occupancy not detailed
    • Physiological conditions that modulate SP1-driven TFR2 expression unknown
  9. 2018 High

    Provided the biochemical basis for TFR2's specificity as a holotransferrin sensor distinct from TFR1.

    Evidence Binding studies with full-length receptors, TFR1-helical-domain chimera, and apical-arm-junction mutagenesis

    PMID:29388418

    Open questions at the time
    • No high-resolution structure of the TFR2-Tf complex
    • Link between binding kinetics and downstream signaling not established
  10. 2023 Medium

    Uncovered additional degradative and non-canonical pathways controlling TFR2: DENND3/RAB12-driven lysosomal degradation, and PFOS-induced ATP5B-dependent mitochondrial translocation.

    Evidence DENND3 p.L708V transfection with lysosomal degradation and pSMAD1/5 readouts plus AAV mouse model; mitochondrial fractionation, ATP5B-TFR2 co-IP, and PFOS mouse model

    PMID:36729283 PMID:36801541

    Open questions at the time
    • Both are single-lab findings in specific disease/toxicant contexts
    • Generality of mitochondrial TFR2 translocation to normal physiology unclear
  11. 2024 Medium

    Demonstrated epigenetic silencing of TFR2 by EZH2-mediated H3K27me3 with consequences for ferroptosis and drug sensitivity in liver cancer.

    Evidence EZH2 gain/loss, H3K27me3 and Pol II ChIP at the TFR2 promoter, ferroptosis and sorafenib-sensitivity assays in HepG2-SR cells

    PMID:38623968

    Open questions at the time
    • Single lab; in vivo relevance to tumor iron handling not established
    • Direct link between TFR2 level and ferroptosis execution not mechanistically dissected
  12. 2026 High

    Showed definitively that TFR2 is required for acute iron-dependent hepcidin/SMAD induction but dispensable for transferrin-iron uptake, separating its sensing function from cargo transport.

    Evidence Hepatocyte-specific Tfr1/Tfr2 double conditional knockouts with fluorescent holo-Tf uptake assays, acute iron challenge, Hamp mRNA, and Smad1,5,9 phosphorylation

    PMID:41662592

    Open questions at the time
    • Precise molecular event linking transferrin occupancy to SMAD phosphorylation still undefined
    • How acute cooperation with HFE differs from chronic non-redundancy not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural mechanism by which holotransferrin occupancy of TFR2 is transduced into BMP-SMAD activation and hepcidin transcription remains undefined.
  • No structure of the assembled HFE/TFR2/HJV ligand-bound complex
  • Conformational/signaling step coupling transferrin binding to SMAD phosphorylation unknown
  • Quantitative integration of MAPK, CD81, and BMP-SMAD inputs into a single hepcidin output not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140299 molecular sensor activity 3 GO:0038024 cargo receptor activity 2 GO:0060089 molecular transducer activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
ATP5BCAV1CD81EPORHFEHJVTFRC
Complex memberships
HFE/TFR2/HJV membrane complexTFR2/CD81 complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Homozygous nonsense mutation in TFR2 causes hereditary hemochromatosis (type 3/HFE3), establishing TFR2 as a gene required for iron homeostasis whose loss leads to iron overload. Genetic mapping and mutation identification in affected families Nature genetics High 10802645
2004 TFR2 is upstream of hepcidin in the iron regulatory pathway: TfR2 mutant mice have lower hepatic hepcidin mRNA and higher duodenal DMT1 expression even after iron loading, while inflammatory stimuli (IL-6, LPS) can still induce hepcidin in TfR2-mutant hepatocytes, indicating TfR2 is required for iron-dependent but not inflammation-dependent hepcidin regulation. Northern blot analysis of hepcidin and DMT1 mRNA in TfR2(Y245X) mutant vs. wild-type mice; iron loading experiments; isolated hepatocyte stimulation with IL-6/LPS Blood High 15345587
2004 TFR2 mutations in patients are associated with low or undetectable urinary hepcidin levels, establishing TFR2 as a modulator of hepcidin production in response to iron in humans. Urinary hepcidin measurement in 10 patients homozygous for TFR2 mutations Blood Medium 15486069
2006 TfR2 is not required for BMP2-, BMP4-, or BMP9-stimulated hepcidin upregulation; BMP signaling acts independently of Tfr2 to regulate hepcidin transcription in isolated hepatocytes. Primary hepatocyte isolation from Tfr2 mutant mice and treatment with BMPs; comparison of hepcidin mRNA induction between wild-type and Tfr2 mutant hepatocytes Proceedings of the National Academy of Sciences of the United States of America High 16801541
2006 TfR2 localizes in lipid raft (low-density Triton-insoluble) plasma membrane domains where it co-immunoprecipitates with caveolin-1 and CD81; activation of TfR2 by holotransferrin or anti-TfR2 antibody activates ERK1/ERK2 and p38 MAP kinases in a lipid raft-dependent manner. TfR2 is also exported in exosomes. Lipid raft biochemical fractionation; co-immunoprecipitation; subcellular fractionation; kinase activation assays; lipid raft disruption experiments; exosome isolation from HepG2 and K562 cells Journal of cell science High 17046995
2009 TfR2 contains a mitochondrial targeting sequence sufficient to import it into mitochondria of substantia nigra dopamine neurons, where it participates in a transferrin/TfR2-mediated iron transport pathway delivering transferrin-bound iron to mitochondria and respiratory complex I; this pathway is redox-sensitive and is disrupted in Parkinson's disease models. Identification of mitochondrial targeting sequence; mitochondrial import assays; co-localization studies; rotenone model of PD; human SN tissue analysis Neurobiology of disease Medium 19250966
2010 Hepatocyte-specific AAV-mediated expression of Tfr2 in Tfr2-deficient mice restores hepcidin mRNA and reduces hepatic iron and transferrin saturation; expression of Hfe in Tfr2-deficient mice had no effect, and vice versa, suggesting Hfe and Tfr2 must both be present and act in the same pathway (complex) to regulate hepcidin, with Hfe being limiting in formation of the Hfe/Tfr2 regulatory complex. AAV2/8 hepatocyte-specific gene delivery of Hfe or Tfr2 in respective knockout mice; measurement of hepcidin mRNA, hepatic iron, and transferrin saturation Blood High 20177050
2010 The alpha isoform of Tfr2 is the hepatic sensor of diferric transferrin required for hepcidin modulation; the beta isoform plays a distinct extrahepatic role—mice lacking only beta-Tfr2 develop spleen iron accumulation with strikingly decreased ferroportin 1 in the spleen, suggesting beta-Tfr2 controls spleen iron efflux, while mice lacking all Tfr2 develop liver iron overload with inadequate hepcidin. Generation and comparison of Tfr2 knockout (KO), beta-Tfr2-lacking knockin (KI), and liver-specific conditional knockout (LCKO-KI) mouse models; iron parameter measurement; hepcidin and Bmp6 mRNA analysis; Fpn1 expression analysis Blood High 20179178
2010 TFR2 plays a prominent role in the hepcidin response to acute oral iron challenge in humans: TFR2-hemochromatosis patients show absent hepcidin response to iron, while HFE-hemochromatosis patients show a blunted but detectable response, placing TFR2 as a primary mediator of acute iron-sensing for hepcidin induction. Serum iron, transferrin saturation, and serum hepcidin measurement by ELISA and mass spectrometry at baseline and after single oral iron dose in hemochromatosis patients and controls Haematologica Medium 21173098
2012 HFE, TfR2, and HJV form a multi-protein membrane complex on the surface of hepatocytes; HFE and TfR2 each bind HJV in a non-competitive manner; residues 120–139 of the TfR2 extracellular domain are required for binding both HFE and HJV; HJV competes with TfR1 for HFE binding, as does TfR2. Glycerol gradient sedimentation assays; co-immunoprecipitation in transfected HuH7 cells; deletion/mutation analysis of TfR2 extracellular domain Journal of hepatology High 22728873
2012 Hfe and Tfr2 are not substrates for Tmprss6; double mutant mice lacking both Tmprss6 and either Hfe or Tfr2 show severe microcytic anemia (driven by Tmprss6 loss/high hepcidin), demonstrating epistasis. Loss of Tfr2 (or Hfe) allows increased erythropoiesis even under high hepcidin, suggesting TFR2 has an erythroid role independent of liver hepcidin regulation. Generation of Hfe/Tmprss6 and Tfr2/Tmprss6 double mutant mice; iron and erythropoiesis parameter measurement Blood cells, molecules & diseases High 22244935
2013 In a stably co-expressing cell system using proximity ligation assay (PLA), Hfe and Tfr2 do not interact with each other; Hfe-Tfr1 interaction and Tfr1-Tfr2 heterodimers are detected, but no Hfe-Tfr2 interaction, challenging the model that direct Hfe-Tfr2 interaction is required for hepcidin regulation. Stable co-expression system; proximity ligation assay; comparison with Hfe-Tfr1 and Tfr1-Tfr2 interactions as positive controls PloS one Medium 24155934
2013 Tfr2 is required for effective upregulation of Bmp6 in response to hepatocyte iron, but not non-parenchymal cell iron; Hfe is not required for Bmp6 upregulation but is required for efficient downstream transmission of the regulatory signal, demonstrating that Hfe and Tfr2 play separate roles in responding to iron in different hepatic cell compartments. Wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice subjected to dietary vs. parenteral iron loading; systematic Bmp6, hepcidin, and Smad signaling analysis American journal of physiology. Gastrointestinal and liver physiology High 24284962
2014 In erythroid cells, TFR2 is a partner of the erythropoietin receptor (EPOR) and stabilizes EPOR on the cell surface; erythroid TFR2 may serve as a sensor of iron deficiency that protects against excessive microcytosis in a way that involves EPOR. Review/synthesis citing experimental data: Tfr2-null erythroid studies, double knockout Tfr2-Tmprss6 mice showing erythroid phenotype differences between global and liver-specific knockouts Frontiers in pharmacology Medium 24847265
2015 CD81 interacts with TfR2 via both cytoplasmic and ecto-transmembrane domains (identified by yeast two-hybrid and co-precipitation); CD81 promotes degradation of TfR2 (knockdown of CD81 increases TfR2 half-life); GRAIL ubiquitin E3 ligase targets CD81 for degradation, which in turn regulates TfR2 levels; the TfR2/CD81 complex is required for maintenance of hepcidin mRNA expression independently of BMP signaling. Yeast two-hybrid screen with TfR2 cytoplasmic domain; co-precipitation with TfR2 domain constructs; siRNA knockdown of CD81 and GRAIL; hepcidin mRNA measurement; BMP6 stimulation; ERK1/2 phosphorylation assays The Journal of biological chemistry High 25635054
2016 Transcription factor Sp1 regulates Tfr2 transcription; downregulation of Sp1 reduces Tfr2 expression, which in turn decreases hepcidin, leading to iron overload. Forced expression of Tfr2 in the liver of Fah(-/-) tyrosinemia mice reduces iron accumulation, confirming the Sp1/Tfr2/hepcidin regulatory axis. Immunoblotting, qRT-PCR, adenovirus transfection for forced Tfr2 expression in Fah(-/-) mice; Sp1 identification as Tfr2 regulator; iron parameter measurements Journal of hepatology Medium 27013087
2018 TfR2 binds holotransferrin through mechanisms distinct from TfR1: the helical domain of TfR2 accounts for differences in the on-rate of transferrin binding; conserved residues at the apical arm junction are critical for TfR2-Tf interaction but not for TfR1-Tf binding; apo-Tf only weakly binds TfR2 at serum pH. Binding studies with full-length receptors; TfR2 chimera containing TfR1 helical domain; mutagenesis of conserved residues at apical arm junction; binding constant determination Biochemistry High 29388418
2003 HFE and TfR2 co-localize in duodenal crypt cells of humans and mice; in human intestinal crypt cells, HFE preferentially interacts with TfR2 in a CD63-negative vesicular compartment (early endosomal transport pathway), and this interaction is enhanced upon exposure to holotransferrin; HFE deficiency disrupts co-localization and alters TfR2 distribution. Confocal microscopy with specific peptide antisera in human/mouse duodenum; co-localization studies in Caco-2 cells; immunohistochemistry in HFE-deficient tissue The journal of histochemistry and cytochemistry Medium 12704209
2023 The DENND3 p.L708V activating variant upregulates RAB12 expression, leading to TFR2 degradation in lysosomes and downstream downregulation of pSMAD1/5 and hepcidin; AAV-mediated expression of the DENND3 p.L708V variant in mice increases serum iron and decreases HAMP and TFR2 expression, establishing the DENND3/RAB12/TFR2 axis in hepcidin regulation. Cell transfection with DENND3 p.L708V vector; TFR2 and hepcidin expression analysis; lysosomal degradation assay; AAV in vivo mouse model; pSMAD1/5 measurement Hepatology international Medium 36729283
2023 Under PFOS exposure, TFR2 and ATP5B are redistributed from the plasma membrane to mitochondria; ATP5B interacts with TFR2; this cooperative translocation mediates mitochondrial iron overload which precedes hepatic insulin resistance. Inhibiting TFR2 translocation to mitochondria reverses PFOS-induced mitochondrial iron overload and insulin resistance. Mitochondrial iron measurement; TFR2 and ATP5B subcellular localization by fractionation; co-immunoprecipitation of ATP5B-TFR2; TFR2 translocation inhibition; siRNA knockdown of ATP5B; plasma-membrane ATP synthase activity assay; mouse PFOS model Ecotoxicology and environmental safety Medium 36801541
2024 EZH2 epigenetically suppresses TFR2 expression by amplifying H3K27me3 modification, reducing RNA polymerase II binding at the TFR2 promoter; reduced TFR2 expression suppresses ferroptosis in hepatocellular carcinoma cells and decreases sorafenib sensitivity. EZH2 overexpression/knockdown; H3K27me3 ChIP analysis; RNA polymerase II binding at TFR2 promoter; TFR2 expression measurement; ferroptosis assays; cell viability; sorafenib sensitivity in HepG2-SR cells Cancer science Medium 38623968
2026 Tfr2 is necessary for acute iron-dependent hepcidin induction in hepatocytes: in mice with hepatocyte-specific ablation of both Tfr1 and Tfr2, acute dietary iron challenge fails to induce Hamp mRNA or Smad1,5,9 phosphorylation, whereas Tfr1-deficient but Tfr2-expressing livers retain this response. Tfr2 is dispensable for transferrin-bound iron uptake by hepatocytes. Tfr2 and Hfe have non-redundant functions under chronic iron loading but cooperate for acute hepcidin induction. Hepatocyte-specific double Tfr1/Tfr2 conditional knockout mice (TfrcAlb-Cre;Tfr2Alb-Cre); fluorescent holo-transferrin (AF647-Tf) uptake assay; dietary iron restriction and acute iron challenge; Hamp mRNA measurement; Smad1,5,9 phosphorylation Blood High 41662592

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nature genetics 627 10802645
2004 Hepcidin is decreased in TFR2 hemochromatosis. Blood 306 15486069
2006 Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proceedings of the National Academy of Sciences of the United States of America 259 16801541
2004 Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 175 15345587
2009 A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease. Neurobiology of disease 156 19250966
2012 The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. Journal of hepatology 146 22728873
2006 TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. Journal of cell science 146 17046995
2002 Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood 78 12130528
2018 Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms. Biochemistry 77 29388418
2010 Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 71 20177050
2010 A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis. Haematologica 66 21173098
2010 Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues. Blood 65 20179178
2010 Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Human molecular genetics 62 21208937
2001 Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5. Nucleic acids research 53 11239002
2004 Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. British journal of haematology 52 15147384
2003 Co-localization of the mammalian hemochromatosis gene product (HFE) and a newly identified transferrin receptor (TfR2) in intestinal tissue and cells. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 45 12704209
2003 AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis. Hepatology research : the official journal of the Japan Society of Hepatology 44 12809944
2014 The extrahepatic role of TFR2 in iron homeostasis. Frontiers in pharmacology 39 24847265
2013 In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2) do not interact. PloS one 37 24155934
2021 IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia. Neurochemical research 35 33835366
2024 EZH2 suppresses ferroptosis in hepatocellular carcinoma and reduces sorafenib sensitivity through epigenetic regulation of TFR2. Cancer science 32 38623968
2023 TFR2 regulates ferroptosis and enhances temozolomide chemo-sensitization in gliomas. Experimental cell research 29 36702193
2008 New TFR2 mutations in young Italian patients with hemochromatosis. Haematologica 27 18245657
2016 Iron overload in hereditary tyrosinemia type 1 induces liver injury through the Sp1/Tfr2/hepcidin axis. Journal of hepatology 26 27013087
2012 Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. Blood cells, molecules & diseases 26 22244935
2012 Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis. Gene 26 22890139
2001 Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload. Blood cells, molecules & diseases 26 11358388
2009 TfR2 expression in human colon carcinomas. Blood cells, molecules & diseases 25 19729324
2016 Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis. International journal of hematology 23 27896572
2018 Long-Term High-Fat Diet Decreases Hepatic Iron Storage Associated with Suppressing TFR2 and ZIP14 Expression in Rats. Journal of agricultural and food chemistry 20 30350980
2006 Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload. Haematologica 19 16923517
2023 Mitochondrial iron overload mediated by cooperative transfer of plasma membrane ATP5B and TFR2 to mitochondria triggers hepatic insulin resistance under PFOS exposure. Ecotoxicology and environmental safety 17 36801541
2015 CD81 promotes both the degradation of transferrin receptor 2 (TfR2) and the Tfr2-mediated maintenance of hepcidin expression. The Journal of biological chemistry 15 25635054
2013 Parenteral vs. oral iron: influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice. American journal of physiology. Gastrointestinal and liver physiology 15 24284962
2006 Hemochromatosis and severe iron overload associated with compound heterozygosity for TFR2 R455Q and two novel mutations TFR2 R396X and G792R. Acta haematologica 15 16424658
2003 Analysis of HFE and TFR2 mutations in selected blood donors with biochemical parameters of iron overload. Haematologica 15 12681966
2013 TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. Blood cells, molecules & diseases 14 24055163
2023 Circ-STC2 promotes the ferroptosis of nucleus pulposus cells via targeting miR-486-3p/TFR2 axis. Journal of orthopaedic surgery and research 13 37480032
2011 Genetic polymorphisms in bovine transferrin receptor 2 (TFR2) and solute carrier family 40 (iron-regulated transporter), member 1 (SLC40A1) genes and their association with beef iron content. Animal genetics 10 22404347
2022 Transferrin receptor 2 (Tfr2) genetic deletion makes transfusion-independent a murine model of transfusion-dependent β-thalassemia. American journal of hematology 9 36071579
2021 New Mutations in HFE2 and TFR2 Genes Causing Non HFE-Related Hereditary Hemochromatosis. Genes 9 34946929
2019 Repeated Restraint Stress Enhances Hepatic TFR2 Expression and Induces Hepatic Iron Accumulation in Rats. Biological trace element research 9 31707638
2005 Analysis of HFE and TFR2 gene mutations in patients with acute leukemia. Leukemia research 8 15863206
2022 Genetic variants in promoter region of TFR2 is associated with the risk of non-alcoholic fatty liver disease in a Chinese Han population: a case-control study. Gastroenterology report 7 36324614
2011 Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis. Revista espanola de enfermedades digestivas 7 21770687
2024 Lack of Hfe and TfR2 in Macrophages Impairs Iron Metabolism in the Spleen and the Bone Marrow. International journal of molecular sciences 6 39273097
2020 Global loss of Tfr2 with concomitant induced iron deficiency greatly ameliorates the phenotype of a murine thalassemia intermedia model. American journal of hematology 6 33180328
2024 Biomimetic peroxidase MOF-Fe promotes bone defect repair by inhibiting TfR2 and activating the BMP2 pathway. Biology direct 5 38654256
2024 Bone marrow Tfr2 deletion improves the therapeutic efficacy of the activin-receptor ligand trap RAP-536 in β-thalassemic mice. American journal of hematology 4 38629683
2023 DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway. Hepatology international 4 36729283
2022 Association of CFI, IL-8, TF and TFR2 Genetic Polymorphisms with Age-Related Macular Degeneration in a Northeastern Chinese Population. Current eye research 4 35180024
2004 Prevalence of HFE and TFR2 gene mutation in 118 Ligurian rheumatic patients. Minerva medica 4 15785438
2022 Assessment of iron overload in a cohort of Sri Lankan patients with transfusion dependent beta thalassaemia and its correlation with pathogenic variants in HBB, HFE, SLC40A1, and TFR2 genes. BMC pediatrics 3 35705926
2020 Role of Slc19a1 and Tfr2 in liver transport of iron and folate: A rat model of folate/iron deficiency followed by supplementation. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 3 32521439
2020 The Proteomics Study of Compounded HFE/TF/TfR2/HJV Genetic Variations in a Thai Family with Iron Overload, Chronic Anemia, and Motor Neuron Disorder. Journal of molecular neuroscience : MN 3 32895881
2018 Tfr2 suppression benefits β-thalassemic erythropoiesis. Blood 3 30467188
2011 [Hyperferritinemia, ferropenia and metabolic syndrome in a patient with a new mutation of gene TFR2 and another in gene FTL. A family study]. Medicina clinica 3 21524769
2001 A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop mutation in the TFR2 gene. Genetic testing 3 11551099
2025 Immunohistochemical investigation of transferrin receptor 2 (TFR2) immunoreactivity in patients with cutaneous lichen planus. Irish journal of medical science 1 41430519
2017 TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood. The Netherlands journal of medicine 1 28276324
2011 [TfR2 mRNA expression in bone marrow mononuclear cells of children with hyperplastic anemia and its implications]. Zhongguo shi yan xue ye xue za zhi 1 21518504
2026 Maternal Adiposity and DNA Methylation of TfR2 and HJV Genes in Early Pregnancy: Mediating Role of Inflammation and Consequences for Iron Status. The Journal of nutrition 0 41651072
2026 Tfr2 is necessary for acute iron-dependent hepcidin induction in mice with Tfr1-deficient hepatocytes. Blood 0 41662592
2026 TFR2 p.A75V mutation aggravates liver iron overload in alcoholic liver disease via ERK pathway. Journal of molecular medicine (Berlin, Germany) 0 41677839
2026 Immunohistochemical investigation of transferrin receptor 2 (TFR2) immunoreactivity in patients with psoriasis vulgaris. Cutaneous and ocular toxicology 0 42126927
2025 Next Generation Sequencing Allows Identification of a Novel Mutation in the TfR2 Gene and Outperforms the Conventional Diagnostic Techniques. EJHaem 0 40574988
2019 Role of TfR2-Y250X and TfR1- rs3817672 Single Nucleotide Polymorphism on Pathophysiology of Iron Deficiency Anemia. The Journal of the Association of Physicians of India 0 31793267
2014 Association between genetic variations in TFR2 gene and coronary heart disease in Chinese: a case-control study. Journal of cardiovascular medicine (Hagerstown, Md.) 0 23751596

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