Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006826 iron ion transport	IBA GO_REF:0000033	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: file:human/TFRC/TFRC-deep-research-perplexity.md See deep research file for comprehensive analysis
GO:0006879 intracellular iron ion homeostasis	IBA GO_REF:0000033	PENDING	Summary: TODO: Review this GOA annotation
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	PENDING	Summary: TODO: Review this GOA annotation
GO:0046718 symbiont entry into host cell	IEA GO_REF:0000108	PENDING	Summary: TODO: Review this GOA annotation
GO:0001618 virus receptor activity	IEA GO_REF:0000043	PENDING	Summary: TODO: Review this GOA annotation
GO:0004998 transferrin receptor activity	IEA GO_REF:0000120	PENDING	Summary: TODO: Review this GOA annotation
GO:0005576 extracellular region	IEA GO_REF:0000044	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	IEA GO_REF:0000120	PENDING	Summary: TODO: Review this GOA annotation
GO:0006897 endocytosis	IEA GO_REF:0000043	PENDING	Summary: TODO: Review this GOA annotation
GO:0006898 receptor-mediated endocytosis	IEA GO_REF:0000117	PENDING	Summary: TODO: Review this GOA annotation
GO:0007165 signal transduction	IEA GO_REF:0000043	PENDING	Summary: TODO: Review this GOA annotation
GO:0033572 transferrin transport	IEA GO_REF:0000120	PENDING	Summary: TODO: Review this GOA annotation
GO:0042470 melanosome	IEA GO_REF:0000044	PENDING	Summary: TODO: Review this GOA annotation
GO:0060586 multicellular organismal-level iron ion homeostasis	IEA GO_REF:0000117	PENDING	Summary: TODO: Review this GOA annotation
GO:0001666 response to hypoxia	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0005615 extracellular space	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0005768 endosome	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0005769 early endosome	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0005905 clathrin-coated pit	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0006953 acute-phase response	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0007584 response to nutrient	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0009897 external side of plasma membrane	IEA GO_REF:0000120	PENDING	Summary: TODO: Review this GOA annotation
GO:0009986 cell surface	IEA GO_REF:0000120	PENDING	Summary: TODO: Review this GOA annotation
GO:0010039 response to iron ion	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0010042 response to manganese ion	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0016020 membrane	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0030316 osteoclast differentiation	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0030544 Hsp70 protein binding	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0032526 response to retinoic acid	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0046688 response to copper ion	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0051087 protein-folding chaperone binding	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0055037 recycling endosome	IEA GO_REF:0000120	PENDING	Summary: TODO: Review this GOA annotation
GO:0055038 recycling endosome membrane	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0070062 extracellular exosome	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0098794 postsynapse	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0098944 postsynaptic recycling endosome membrane	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0099072 regulation of postsynaptic membrane neurotransmitter receptor levels	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:1990712 HFE-transferrin receptor complex	IEA GO_REF:0000107	PENDING	Summary: TODO: Review this GOA annotation
GO:0005515 protein binding	IPI PMID:14691533 Mechanism for multiple ligand recognition by the human trans...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:14691533 Mechanism for multiple ligand recognition by the human transferrin receptor.
GO:0005515 protein binding	IPI PMID:15965644 The Q283P amino-acid change in HFE leads to structural and f...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:15965644 Jun 18. The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein.
GO:0005515 protein binding	IPI PMID:16271884 The molecular mechanism for receptor-stimulated iron release...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:16271884 The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin.
GO:0005515 protein binding	IPI PMID:16325581 TTP specifically regulates the internalization of the transf...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:16325581 TTP specifically regulates the internalization of the transferrin receptor.
GO:0005515 protein binding	IPI PMID:16354665 Release of the soluble transferrin receptor is directly regu...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:16354665 2005 Dec 14. Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin.
GO:0005515 protein binding	IPI PMID:20133674 Binding and uptake of H-ferritin are mediated by human trans...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:20133674 Binding and uptake of H-ferritin are mediated by human transferrin receptor-1.
GO:0005515 protein binding	IPI PMID:20404192 Noncanonical interactions between serum transferrin and tran...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:20404192 Noncanonical interactions between serum transferrin and transferrin receptor evaluated with electrospray ionization mass spectrometry.
GO:0005515 protein binding	IPI PMID:20618438 N-glycosylation is important for the correct intracellular l...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:20618438 2010 Jul 5. N-glycosylation is important for the correct intracellular localization of HFE and its ability to decrease cell surface transferrin binding.
GO:0005515 protein binding	IPI PMID:21788477 How the binding of human transferrin primes the transferrin ...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation 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.	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation 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 ...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:29950717 Jun 27. 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.	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:32296183 Apr 8. 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:20208545 Mar 7. Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses.
GO:0042802 identical protein binding	IPI PMID:23384347 The transferrin receptor-1 membrane stub undergoes intramemb...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23384347 The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b.
GO:0042802 identical protein binding	IPI PMID:29302006 Transferrin receptor 1 is a reticulocyte-specific receptor f...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:29302006 Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax.
GO:0004998 transferrin receptor activity	IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9465039 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
GO:0006898 receptor-mediated endocytosis	IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9465039 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
GO:0007166 cell surface receptor signaling pathway	IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9465039 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
GO:0033572 transferrin transport	IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9465039 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
GO:0004998 transferrin receptor activity	IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:18353247 Epub 2008 Mar 7. HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron.
GO:0033572 transferrin transport	IDA PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:18353247 Epub 2008 Mar 7. HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron.
GO:0005764 lysosome	IDA GO_REF:0000052	PENDING	Summary: TODO: Review this GOA annotation
GO:0005768 endosome	IDA GO_REF:0000052	PENDING	Summary: TODO: Review this GOA annotation
GO:0005515 protein binding	IPI PMID:38625739 The secreted micropeptide C4orf48 enhances renal fibrosis vi...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0004998 transferrin receptor activity	IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0060586 multicellular organismal-level iron ion homeostasis	IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5691154	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8866277	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867754	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867756	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868071	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868072	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868230	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868236	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868648	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868651	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868661	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-917807	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-917814	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-917839	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-917987	PENDING	Summary: TODO: Review this GOA annotation
GO:0005886 plasma membrane	IDA PMID:23137377 Quantitative targeted absolute proteomic analysis of transpo...	PENDING	Summary: TODO: Review this GOA annotation 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.	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back.
GO:0010637 negative regulation of mitochondrial fusion	IMP PMID:26214738 Regulation of mitochondrial morphology and function by stear...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26214738 Regulation of mitochondrial morphology and function by stearoylation of TFR1.
GO:0035556 intracellular signal transduction	IMP PMID:26214738 Regulation of mitochondrial morphology and function by stear...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26214738 Regulation of mitochondrial morphology and function by stearoylation of TFR1.
GO:0150104 transport across blood-brain barrier	NAS PMID:26590417 Establishment and Dysfunction of the Blood-Brain Barrier.	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26590417 Establishment and Dysfunction of the Blood-Brain Barrier.
GO:0010628 positive regulation of gene expression	IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:0043066 negative regulation of apoptotic process	IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:1900182 positive regulation of protein localization to nucleus	IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:0005515 protein binding	IPI PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:0019901 protein kinase binding	IPI PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:0031334 positive regulation of protein-containing complex assembly	IMP PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:0044877 protein-containing complex binding	IPI PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-N...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:23016877 TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
GO:0005515 protein binding	IPI PMID:29388418 Transferrin Receptors TfR1 and TfR2 Bind Transferrin through...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:29388418 Epub 2018 Feb 12. 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:18619525 Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868658	PENDING	Summary: TODO: Review this GOA annotation
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868659	PENDING	Summary: TODO: Review this GOA annotation
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868660	PENDING	Summary: TODO: Review this GOA annotation
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868661	PENDING	Summary: TODO: Review this GOA annotation
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8869438	PENDING	Summary: TODO: Review this GOA annotation
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8871193	PENDING	Summary: TODO: Review this GOA annotation
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8871194	PENDING	Summary: TODO: Review this GOA annotation
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917807	PENDING	Summary: TODO: Review this GOA annotation
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917814	PENDING	Summary: TODO: Review this GOA annotation
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917835	PENDING	Summary: TODO: Review this GOA annotation
GO:0010008 endosome membrane	IDA PMID:16380373 Sec14 homology domain targets p50RhoGAP to endosomes and pro...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:16380373 2005 Dec 27. Sec14 homology domain targets p50RhoGAP to endosomes and provides a link between Rab and Rho GTPases.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:16380373 Sec14 homology domain targets p50RhoGAP to endosomes and pro...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:16380373 2005 Dec 27. Sec14 homology domain targets p50RhoGAP to endosomes and provides a link between Rab and Rho GTPases.
GO:0031410 cytoplasmic vesicle	IDA PMID:15229288 Over-expression of Rififylin, a new RING finger and FYVE-lik...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:15229288 2004 Jun 30. Over-expression of Rififylin, a new RING finger and FYVE-like domain-containing protein, inhibits recycling from the endocytic recycling compartment.
GO:0005515 protein binding	IPI PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0042102 positive regulation of T cell proliferation	IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0045830 positive regulation of isotype switching	IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0031623 receptor internalization	IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0033572 transferrin transport	IDA PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:26642240 A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
GO:0005515 protein binding	IPI PMID:9990067 Association of HFE protein with transferrin receptor in cryp...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9990067 Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum.
GO:0016323 basolateral plasma membrane	IDA PMID:9990067 Association of HFE protein with transferrin receptor in cryp...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9990067 Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum.
GO:1990712 HFE-transferrin receptor complex	IDA PMID:9990067 Association of HFE protein with transferrin receptor in cryp...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9990067 Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum.
GO:0005515 protein binding	IPI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:18353247 Epub 2008 Mar 7. HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron.
GO:0005886 plasma membrane	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:18353247 Epub 2008 Mar 7. HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron.
GO:0009897 external side of plasma membrane	IGI PMID:18353247 HFE association with transferrin receptor 2 increases cellul...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:18353247 Epub 2008 Mar 7. HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron.
GO:0005515 protein binding	IPI PMID:9546397 Crystal structure of the hemochromatosis protein HFE and cha...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9546397 Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
GO:0042803 protein homodimerization activity	IPI PMID:9546397 Crystal structure of the hemochromatosis protein HFE and cha...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9546397 Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
GO:1990712 HFE-transferrin receptor complex	IDA PMID:9546397 Crystal structure of the hemochromatosis protein HFE and cha...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9546397 Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
GO:0005515 protein binding	IPI PMID:9465039 The hemochromatosis gene product complexes with the transfer...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9465039 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
GO:1990712 HFE-transferrin receptor complex	IDA PMID:9465039 The hemochromatosis gene product complexes with the transfer...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:9465039 The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
GO:1903561 extracellular vesicle	HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:24769233 2014 Apr 24. 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:16254249 Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis.
GO:0055037 recycling endosome	IDA PMID:24561039 Rab11 endosomes contribute to mitotic spindle organization a...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:24561039 2014 Feb 20. Rab11 endosomes contribute to mitotic spindle organization and orientation.
GO:0055037 recycling endosome	IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:22456507 2012 Mar 28. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy.
GO:0001558 regulation of cell growth	IMP NOT PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human...	PENDING	Summary: TODO: Review this GOA 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human p97.
GO:0009986 cell surface	IDA PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human p97.
GO:0042127 regulation of cell population proliferation	IMP NOT PMID:7556058 A novel iron uptake mechanism mediated by GPI-anchored human...	PENDING	Summary: TODO: Review this GOA 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:22658674 May 31. 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:22516433 Epub 2012 Apr 10. 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 ...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:22664934 Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach.
GO:0003725 double-stranded RNA binding	IDA PMID:21266579 Raftlin is involved in the nucleocapture complex to induce p...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:21266579 2011 Jan 25. 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:20458337 2010 May 11. 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...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:20202662 2010 Mar 3. Ebola virus uses clathrin-mediated endocytosis as an entry pathway.
GO:0005905 clathrin-coated pit	IDA PMID:12857860 Myo6 facilitates the translocation of endocytic vesicles fro...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:12857860 Mar 20. Myo6 facilitates the translocation of endocytic vesicles from cell peripheries.
GO:0005768 endosome	IDA PMID:14612438 Zn2+-stimulated endocytosis of the mZIP4 zinc transporter re...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:14612438 Nov 11. Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane.
GO:0004998 transferrin receptor activity	TAS PMID:10192390 Transferrin receptor is necessary for development of erythro...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:10192390 Transferrin receptor is necessary for development of erythrocytes and the nervous system.
GO:0005768 endosome	TAS PMID:8394993 Differential effects of antimycin A on endocytosis and exocy...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:8394993 Differential effects of antimycin A on endocytosis and exocytosis of transferrin also are observed for internalization and externalization of beta-adrenergic receptors.
GO:0005886 plasma membrane	TAS PMID:6090955 Primary structure of human transferrin receptor deduced from...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells.
GO:0006879 intracellular iron ion homeostasis	NAS PMID:1871153 Characterization of transferrin receptor released by K562 er...	PENDING	Summary: TODO: Review this GOA annotation 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...	PENDING	Summary: TODO: Review this GOA annotation Supporting Evidence: PMID:1871153 Characterization of transferrin receptor released by K562 erythroleukemia cells.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

PMID:10192390

Transferrin receptor is necessary for development of erythrocytes and the nervous system.

PMID:10638746

Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor.

PMID:12857860

Myo6 facilitates the translocation of endocytic vesicles from cell peripheries.

PMID:14612438

Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane.

PMID:14691533

Mechanism for multiple ligand recognition by the human transferrin receptor.

PMID:15229288

Over-expression of Rififylin, a new RING finger and FYVE-like domain-containing protein, inhibits recycling from the endocytic recycling compartment.

PMID:15965644

The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein.

PMID:16254249

Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis.

PMID:16271884

The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin.

PMID:16325581

TTP specifically regulates the internalization of the transferrin receptor.

PMID:16354665

Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin.

PMID:16380373

Sec14 homology domain targets p50RhoGAP to endosomes and provides a link between Rab and Rho GTPases.

PMID:18353247

HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron.

PMID:18619525

Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation.

PMID:1871153

Characterization of transferrin receptor released by K562 erythroleukemia cells.

PMID:20133674

Binding and uptake of H-ferritin are mediated by human transferrin receptor-1.

PMID:20202662

Ebola virus uses clathrin-mediated endocytosis as an entry pathway.

PMID:20208545

Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses.

PMID:20404192

Noncanonical interactions between serum transferrin and transferrin receptor evaluated with electrospray ionization mass spectrometry.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:20618438

N-glycosylation is important for the correct intracellular localization of HFE and its ability to decrease cell surface transferrin binding.

PMID:21266579

Raftlin is involved in the nucleocapture complex to induce poly(I:C)-mediated TLR3 activation.

PMID:21788477

How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH.

PMID:22456507

Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy.

PMID:22516433

Proteomic analysis of microvesicles from plasma of healthy donors reveals high individual variability.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22664934

Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach.

PMID:23016877

TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.

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.

PMID:23384347

The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b.

PMID:24561039

Rab11 endosomes contribute to mitotic spindle organization and orientation.

PMID:24769233

Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:26214738

Regulation of mitochondrial morphology and function by stearoylation of TFR1.

PMID:26590417

Establishment and Dysfunction of the Blood-Brain Barrier.

PMID:26642240

A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

PMID:29302006

Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax.

PMID:29388418

Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms.

PMID:29950717

Cryo-EM structure of an essential Plasmodium vivax invasion complex.

PMID:30280653

Blood-Brain Barrier: From Physiology to Disease and Back.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:38625739

The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

PMID:6090955

Primary structure of human transferrin receptor deduced from the mRNA sequence.

PMID:7556058

A novel iron uptake mechanism mediated by GPI-anchored human p97.

PMID:8394993

Differential effects of antimycin A on endocytosis and exocytosis of transferrin also are observed for internalization and externalization of beta-adrenergic receptors.

PMID:9465039

The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.

PMID:9546397

Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.

PMID:9990067

Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum.

Reactome:R-HSA-5691154

HFE binds TFRC dimer

Reactome:R-HSA-8866277

AP-2 directly binds some endocytic cargo

Reactome:R-HSA-8867754

F- and N- BAR domain proteins bind the clathrin-coated pit

Reactome:R-HSA-8867756

CLASP proteins and cargo are recruited to the nascent clathrin-coated pit

Reactome:R-HSA-8868071

Clathrin recruits PIK3C2A

Reactome:R-HSA-8868072

Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2

Reactome:R-HSA-8868230

SNX9 recruits components of the actin polymerizing machinery

Reactome:R-HSA-8868236

BAR domain proteins recruit dynamin

Reactome:R-HSA-8868648

SYNJ hydrolyze PI(4,5)P2 to PI(4)P

Reactome:R-HSA-8868651

Endophilins recruit synaptojanins to the clathrin-coated pit

Reactome:R-HSA-8868658

HSPA8-mediated ATP hydrolysis promotes vesicle uncoating

Reactome:R-HSA-8868659

Clathrin recruits auxilins to the clathrin-coated vesicle

Reactome:R-HSA-8868660

Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle

Reactome:R-HSA-8868661

Dynamin-mediated GTP hydrolysis promotes vesicle scission

Reactome:R-HSA-8869438

Dissociation of clathrin-associated proteins

Reactome:R-HSA-8871193

Dissociation of AAK1 and dephosphorylation of AP-2 mu2

Reactome:R-HSA-8871194

RAB5 and GAPVD1 bind AP-2

Reactome:R-HSA-917807

holoTF:TFRC dimer translocates from plasma membrane to endosome membrane

Reactome:R-HSA-917814

apoTF:TFRC dimer translocates from endosome membrane to plasma membrane

Reactome:R-HSA-917835

Fe3+ dissociates from holoTF:TFRC dimer

Reactome:R-HSA-917839

apo-Transferrin dissociates from the receptor complex

Reactome:R-HSA-917987

TFRC dimer binds 2xholoTF

file:human/TFRC/TFRC-deep-research-perplexity.md

Deep research on TFRC function

📚 Additional Documentation

Deep Research Perplexity

(TFRC-deep-research-perplexity.md)

provider: perplexity
model: sonar-deep-research
cached: false
start_time: '2025-12-12T07:11:18.686217'
end_time: '2025-12-12T07:13:38.216954'
duration_seconds: 139.53
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: TFRC
gene_symbol: TFRC
uniprot_accession: P02786
protein_description: 'RecName: Full=Transferrin receptor protein 1; Short=TR; Short=TfR;
Short=TfR1; Short=Trfr; AltName: Full=T9; AltName: Full=p90; AltName: CD_antigen=CD71;
Contains: RecName: Full=Transferrin receptor protein 1, serum form; Short=sTfR;'
gene_info: Name=TFRC;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the peptidase M28 family. M28B subfamily.
protein_domains: PA_dom_sf. (IPR046450); PA_domain. (IPR003137); Peptidase_M28.
(IPR007484); Peptidase_M28B. (IPR039373); TFR-like_dimer_dom. (IPR007365)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
reasoning_effort: medium
search_domain_filter: []
return_citations: true
temperature: 0.0
citation_count: 56

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P02786
Protein Description: RecName: Full=Transferrin receptor protein 1; Short=TR; Short=TfR; Short=TfR1; Short=Trfr; AltName: Full=T9; AltName: Full=p90; AltName: CD_antigen=CD71; Contains: RecName: Full=Transferrin receptor protein 1, serum form; Short=sTfR;
Gene Information: Name=TFRC;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the peptidase M28 family. M28B subfamily.
Key Domains: PA_dom_sf. (IPR046450); PA_domain. (IPR003137); Peptidase_M28. (IPR007484); Peptidase_M28B. (IPR039373); TFR-like_dimer_dom. (IPR007365)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "TFRC" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'TFRC' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene TFRC (gene ID: TFRC, UniProt: P02786) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Let me analyze this task carefully. The user wants a comprehensive research report on the TFRC gene (transferrin receptor protein 1, CD71) in humans. The UniProt accession is P02786.

Let me verify the context:
1. Gene symbol: TFRC ✓
2. Protein: Transferrin receptor protein 1 (TfR1, CD71) ✓
3. Organism: Homo sapiens (Human) ✓
4. UniProt: P02786 ✓

The search results provided contain extensive information about TFRC/TfR1. Let me organize my findings into major themes for the report structure.

Major themes to cover:
1. Molecular Structure and Basic Function - Structure of the protein, transmembrane organization, domains
2. Iron Transport Mechanisms - How TfR1 binds and internalizes iron-loaded transferrin
3. Intracellular Trafficking Pathway - Endocytosis, sorting, recycling
4. Regulation and Post-translational Modifications - How expression is regulated (iron-responsive elements), how the protein is modified
5. Interactions and Cellular Partners - HFE interactions, other binding partners
6. Clinical and Biological Significance - Role in disease, erythropoiesis, cancer
7. Specialized Functions - Blood-brain barrier transport, ferritin binding, viral interactions
8. Therapeutic Applications - Anti-TfR1 antibodies, drug delivery strategies

Let me now write a comprehensive 10,000+ word report based on the search results provided, making sure to:
- Cite all major claims
- Use flowing paragraphs instead of lists
- Maintain academic tone
- Cover all the required aspects
- Ensure proper narrative flow

Transferrin Receptor Protein 1 (TFRC): A Comprehensive Analysis of Molecular Structure, Function, and Biological Significance

Executive Summary

Transferrin receptor protein 1 (TfR1), also designated as cluster of differentiation 71 (CD71), represents one of the most extensively characterized iron transport proteins in humans, encoded by the TFRC gene located on chromosome 3[1][3]. As a cell surface glycoprotein expressed on virtually all nucleated cells, TfR1 functions as the primary gateway for cellular iron acquisition through receptor-mediated endocytosis of iron-bound transferrin molecules[10][32]. The protein's significance extends well beyond basic iron homeostasis, encompassing critical roles in erythropoiesis, proliferation of rapidly dividing cells, and emerging therapeutic applications in cancer treatment and drug delivery to the brain. Understanding TfR1's molecular mechanisms, regulatory pathways, and biological contexts illuminates fundamental principles of cellular nutrient acquisition and reveals potential vulnerabilities that cancer cells exploit to support their elevated metabolic demands. This comprehensive report synthesizes current knowledge regarding TfR1's structure, function, intracellular trafficking, regulation, and clinical relevance, providing a detailed mechanistic foundation for understanding how this receptor orchestrates iron import and influences cellular physiology across diverse biological contexts.

Molecular Structure and Protein Architecture

Transmembrane Organization and Structural Domains

TfR1 is a transmembrane glycoprotein composed fundamentally of two disulfide-linked monomers, each approximately 90 kilodaltons in size, creating a functional homodimer at the cell surface[1][2][27]. The protein architecture comprises a single transmembrane domain with an extracellular ectodomain containing the iron and transferrin binding regions, a membrane-proximal region, and a relatively short cytoplasmic tail of approximately 67 amino acids[1][47]. The two polypeptide chains are covalently linked by disulfide bonds at residues 89 and 98, positioned immediately extracellular to the transmembrane domain, which provides structural stability to the dimeric complex[15]. Notably, crystallographic studies have revealed that the disulfide-linked dimeric structure, while providing stability, is not absolutely essential for the protein's functional activity, as non-covalently linked dimers retain substantial iron transport capacity[27].

The three-dimensional structure of the TfR1 ectodomain reveals three distinct functional domains arranged within each monomeric subunit[49][52]. One domain exhibits striking structural similarity to carboxypeptidases and aminopeptidases, belonging to the M28 family of zinc-dependent proteases, though TfR1 itself is catalytically inactive as a peptidase[43][49]. This protease-like domain participates critically in both transferrin binding and in stabilizing the conformational changes necessary for iron release from transferrin within acidic endosomal compartments[49][60]. The remaining domains include an apical domain and a helical domain, each contributing essential interactions with ligand molecules and mediating conformational changes during the iron transport cycle[60]. The structural organization positions these domains to facilitate binding of iron-laden transferrin at physiological pH on the cell surface while simultaneously preparing the receptor for the conformational rearrangements triggered by endosomal acidification[49][52].

Post-Translational Modifications and Chemical Modifications

TfR1 undergoes multiple post-translational modifications that influence its localization, stability, and functional activity. Each monomeric chain is extensively glycosylated, with N-linked carbohydrate moieties contributing to protein stability, trafficking, and potentially immune recognition[1][2]. Additionally, the protein is palmitoylated at the inner membrane surface, a lipid modification occurring on intracellular cysteine residues that enhances membrane association and may influence lateral mobility within the plasma membrane[1][26]. The cytoplasmic domain contains a unique phosphorylation site at serine residue 24, though surprisingly, phosphorylation at this site does not appear critical for the protein's endocytic function or basolateral sorting in polarized cells[58]. This observation suggests that while phosphorylation occurs in response to kinase activity, it may not constitute an essential regulatory mechanism for basal iron transport function, though it might modulate responses to specific cellular signals or growth factors.

Iron Transport Function and Cellular Iron Acquisition

Molecular Mechanism of Transferrin Binding and Internalization

The primary physiological function of TfR1 involves binding iron-loaded transferrin (holo-transferrin) at the cell surface and mediating its entry into cells through clathrin-dependent endocytosis[2][7][10]. Iron in plasma exists in a highly restricted form, primarily bound to transferrin, an 85-kilodalton transport protein carrying up to two ferric iron (Fe³⁺) atoms in two distinct binding sites designated the C-terminal lobe and N-terminal lobe[2][15]. TfR1 exhibits striking selectivity for diferric transferrin over iron-free apotransferrin at neutral pH, creating a mechanism that ensures cells preferentially import iron-loaded molecules while generally excluding iron-depleted transferrin from cellular uptake[15][57]. The C-lobe and N-lobe of transferrin each interact with distinct regions of the TfR1 ectodomain, with the C-lobe engaging the helical domain of the receptor while the N-lobe contacts the stalk region[57].

Upon holo-transferrin binding, the transferrin-TfR1 complex undergoes rapid clustering within specialized plasma membrane invaginations called coated pits, which are lined with the clathrin scaffolding protein[1][7]. The formation of these coated pits requires multiple machinery components, including the clathrin complex itself, adaptor proteins, and dynamin, a GTPase essential for membrane scission[7]. Within these coated structures, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) plays a critical regulatory role, as inactivation of this phospholipid directly reduces transferrin internalization and increases surface levels of TfR1, demonstrating the importance of lipid composition in regulating this entry pathway[7]. The internalized transferrin-receptor complex is transported in clathrin-coated vesicles that rapidly lose their clathrin coats and fuse with early endosomal compartments within minutes of internalization[7][9].

Iron Release and Endosomal Sorting

Once internalized into early endosomes, a critical pH-dependent conformational change occurs that dramatically alters the transferrin-TfR1 interaction and enables iron release[5][15][57]. The early endosomal compartment maintains a pH of approximately 5.0-6.0, maintained by vacuolar ATPase proton pumps, which creates an acidic microenvironment promoting protonation of histidine residues within both transferrin and the receptor[2][5]. This acidification triggers dramatic conformational changes in the transferrin molecule, particularly affecting the iron binding sites and the interaction interfaces between transferrin and its receptor[57][60]. Specifically, protonation of His349 in the C-terminal lobe at acidic pH converts a hydrophobic interaction with Phe760 of the TfR into a stronger cation-π interaction or salt bridge with Asp757, causing a conformational change that destabilizes the iron binding cleft in the C-lobe[60]. Simultaneously, the N-lobe undergoes movement of its PRKP loop that disrupts the N2 subdomain's interaction with the receptor, allowing the iron binding cleft to open and release the iron atom[60].

Critically, the transferrin receptor itself undergoes ligand-dependent conformational changes that actively promote iron release from transferrin at acidic pH[5][60]. The binding of iron-loaded transferrin causes rotation at the TfR1 dimer interface, bringing four critical histidine residues (His475 in each protease-like domain and His684 in each helical domain) into proximity[60]. These conformational changes at the dimer interface prime the receptor to undergo additional pH-induced movements when exposed to endosomal acidification, directly facilitating the conformational changes in transferrin that enable iron dissociation[60]. This active role of the receptor in stimulating iron release represents a sophisticated mechanism ensuring efficient iron delivery into the cell[5]. Additionally, within endosomes, the ferric iron (Fe³⁺) released from transferrin is rapidly reduced to ferrous iron (Fe²⁺) by metalloproteases, notably STEAP3, a process essential for subsequent iron export from the endosome[2].

Iron Export and Intracellular Distribution

Once iron is released from transferrin within acidic endosomes, the ferrous iron (Fe²⁺) must be transported across the endosomal membrane into the cytoplasm through the action of divalent metal transporter 1 (DMT1, also called SLC11A2)[2][14]. DMT1 functions as a proton-coupled iron transporter, with the acidic endosomal environment providing the proton gradient necessary to drive iron uptake across the endosomal membrane[2][14]. Once in the cytoplasm, iron faces three potential metabolic fates depending on cellular needs[2]. Iron may be immediately incorporated into ferritin, a 24-subunit iron storage protein that safely sequesters iron in mineral form as ferrihydrite, protecting against the generation of reactive oxygen species through Fenton chemistry[2][14]. Alternatively, iron may be transported to mitochondria for incorporation into heme groups and iron-sulfur clusters, essential cofactors in the electron transport chain and numerous metabolic enzymes[2][40]. Finally, iron may be exported back into the extracellular environment through ferroportin (SLC40A1), the only known cellular iron exporter, allowing iron redistribution to other tissues[2][14].

The export of iron through ferroportin is tightly regulated by hepcidin, a circulating peptide hormone produced by hepatocytes that binds ferroportin and triggers its ubiquitin-mediated degradation, thereby preventing iron export and causing cellular iron retention[14]. This systemic hormone represents the critical control point for whole-body iron homeostasis, linking iron sensing in the liver to the regulation of iron absorption in the intestine and iron recycling in macrophages[14]. Understanding this regulatory axis proves essential for comprehending both normal iron metabolism and iron overload disorders.

Intracellular Trafficking Pathway and Receptor Recycling

Clathrin-Mediated Endocytosis and Early Endosomal Sorting

The internalization of transferrin receptor and its ligand occurs through well-characterized clathrin-mediated endocytosis, involving recruitment of the receptor into coated pits through interactions with adaptor protein complexes[7][49]. The AP2 adaptor complex, comprising four subunits (α, β, μ, and σ), binds directly to a critical YXRF internalization motif (where Y is tyrosine, X is any amino acid, R is arginine, and F is phenylalanine) located within the cytoplasmic tail of TfR1[58]. This motif appears to form a tight turn structure that is specifically recognized by adaptor proteins, ensuring efficient clustering of the receptor into coated pits[58]. Once internalized into clathrin-coated vesicles, the vesicles rapidly lose their clathrin coat through the action of uncoating proteins, exposing the underlying transport vesicle to fusion machinery[7].

The early endosomal compartment represents a highly dynamic sorting station where cargo molecules are distributed to distinct cellular destinations based on their biochemical properties[7][9]. Early endosomes exist in two functionally distinct populations—dynamic early endosomes that mature through transitional stages, and static early endosomes that remain relatively stable[7]. The sorting of transferrin at the cell surface appears to begin immediately upon binding and receptor clustering, with early segregation occurring through TIRF (Total Internal Reflection Fluorescence) microscopy-visualized mechanisms within 100-200 nanometers of the plasma membrane[7]. This pre-endosomal sorting suggests that the cell possesses mechanisms for distinguishing cargo molecules even before their entry into membrane-enclosed compartments, potentially through preferential inclusion in distinct lipid microdomains or through interactions with specific sorting proteins[7].

Recycling Endosome Trafficking and Plasma Membrane Return

Following iron release in early endosomes, both the transferrin receptor and iron-depleted transferrin (apotransferrin) must be recycled back to the cell surface to complete the iron transport cycle and to allow transferrin molecules to acquire new iron in the bloodstream[7][9]. This recycling process is mediated through recycling endosomes, specialized compartments enriched in the Rab11 GTPase, which functions as a crucial regulator of membrane trafficking from recycling endosomes back to the plasma membrane[7][59]. Real-time fluorescence microscopy studies have revealed that transferrin moves into tubular formations in both static and dynamic early endosomes before separating, with these vesicles then delivering transferrin to either the perinuclear recycling compartment or directly back to the plasma membrane[7]. The perinuclear recycling compartment, marked by Rab11 localization, represents a major hub for receptor sorting and redistribution[7][59].

Multiple small GTPases of the Rab family regulate distinct steps of the transferrin recycling pathway, with Rab4, localized primarily in early endosomes, mediating rapid recycling of some transferrin receptor molecules directly from early endosomes to the plasma membrane[7]. Overexpression of Rab4 causes accumulation of transferrin in tubular structures and vesicles directed toward the recycling compartment, suggesting that Rab4 modulates the velocity and efficiency of recycling[7]. The GEF Grab (guanine nucleotide exchange factor for Rab8) has emerged as another critical regulator of transferrin receptor recycling specifically in erythroid cells, with GRAB knockdown reducing transferrin-bound iron uptake and causing hypochromic-microcytic anemia in mouse models[37]. The exocyst, a multiprotein complex involved in tethering recycling vesicles to the plasma membrane, appears to be recruited by active Rab8 in a Grab-dependent manner, providing a molecular link between Rab GTPase activation and vesicle fusion[37].

Sorting Between Recycling and Lysosomal Degradation

While TfR1 is predominantly recycled back to the plasma membrane to maintain high iron import capacity, constitutive degradation of the receptor also occurs through a specialized Rab12-dependent pathway[59]. Small GTPase Rab12 and its upstream activator Dennd3 regulate the trafficking of TfR1 from recycling endosomes to lysosomes, with Rab12 activation promoting TfR1 degradation[59]. This constitutive degradation pathway appears distinct from conventional endocytic degradation through late endosomes and multivesicular bodies, instead operating through direct trafficking from recycling endosomes to lysosomes[59]. The physiological significance of this basal degradation pathway remains unclear but may provide a mechanism for modulating TfR1 levels independent of iron-responsive transcriptional regulation[59].

Additionally, under conditions of iron excess, TfR1 undergoes iron-induced selective degradation through lysosomal pathways, providing a mechanism to reduce iron uptake capacity when intracellular iron levels become elevated[59]. This iron-regulated degradation complements the transcriptional downregulation of TfR1 mediated through iron-responsive elements, creating multiple levels of control over iron import capacity[59]. Importantly, recent studies employing cryo-electron microscopy have revealed structural details of how the transferrin receptor interacts with its ligands in the endosomal environment, showing that the apical domain of TfR1 mediates binding to heavy-chain ferritin through a distinct set of epitopes compared to those used for transferrin binding, allowing differential regulation of iron acquisition from these two sources[22].

Regulation of Transferrin Receptor Expression

Iron-Responsive Element Regulation

The cellular abundance of transferrin receptor is tightly regulated by iron status through a sophisticated post-transcriptional mechanism involving iron-responsive elements (IREs) and iron regulatory proteins (IRPs)[31][34]. The 3′ untranslated region (3′ 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[31][34]. Under conditions of low intracellular iron, these IRPs bind avidly to the TFRC IREs, stabilizing the mRNA and preventing its degradation[31][34]. The protective effect of IRP binding appears mediated through blocking access of endonucleases to the unstable regions within the 3′ UTR, as mutagenesis studies have identified multiple non-IRE stem-loops contributing minimally to mRNA instability but enhancing instability when IRP protection is lost[31].

When intracellular iron levels rise, IRP1 undergoes an iron-sulfur cluster (Fe-S) assembly that converts it into an aconitase-like conformation unsuitable for IRE binding, causing its release from the TFRC mRNA and allowing the mRNA to be rapidly degraded[34]. IRP2, by contrast, is ubiquitinated and proteasomally degraded under iron-replete conditions[34]. This iron-sensing mechanism achieves remarkable specificity through direct iron binding to the IRE itself, which induces conformational changes favoring eIF4F (eukaryotic Initiation Factor 4F) binding over IRP binding, creating a conformational switch that responds to iron status[14][34]. The regulatory response appears graded rather than switch-like, with progressive loss of IRP protection occurring as iron levels increase, allowing cells to fine-tune TfR1 expression in response to cellular iron demands[31].

Transcriptional and Signal-Responsive Regulation

Beyond the iron-responsive post-transcriptional regulation, TfR1 expression is modulated by multiple transcriptional and signaling pathways responding to cellular growth, differentiation signals, and metabolic states[1][2]. Growth factors including insulin and insulin-like growth factors upregulate TfR1 expression, reflecting increased iron demands of proliferating cells[2]. Erythropoietin (EPO), a key regulator of red blood cell production, strongly induces TfR1 expression in erythroid progenitors, enabling the massive iron uptake necessary for hemoglobin synthesis during erythropoiesis[40]. The transcriptional upregulation of TFRC during erythroid differentiation occurs through multiple pathways, including the GATA1 transcription factor crucial for erythroid-specific gene expression, demonstrating integration of iron metabolism control with the physiological demands of hematopoiesis[40].

Interestingly, TFRC expression is also regulated through alternative splicing mechanisms responsive to iron status and cellular context, with evidence suggesting that the transferrin receptor itself possesses RNA-binding protein properties influencing splicing patterns of genes involved in iron metabolism, DNA repair, and translation[36]. This newly appreciated function of TfR1 as an RNA-binding protein adds an additional layer of complexity to iron metabolism regulation, suggesting that TfR1 may coordinate iron uptake with cellular processes dependent on iron availability at the transcriptional level[36].

Protein Interactions and Functional Partnerships

Interaction with HFE and Regulation of Hepcidin Expression

A critical interaction occurs between TfR1 and HFE (hemochromatosis protein), the protein mutated in hereditary hemochromatosis type 1[20][23]. HFE interacts with TfR1 through the α1 and α2 domains of HFE and functions as a regulatory cofactor that modulates the iron-sensing properties of the transferrin receptor system[20][23]. The HFE-TfR1 complex appears to interact with TfR2 (transferrin receptor 2), creating a supramolecular complex involved in iron sensing and signaling to regulate hepcidin expression, the master hormone controlling systemic iron homeostasis[20]. The TfR2/HFE complex detects iron-loaded transferrin and triggers activation of BMP-SMAD signaling pathways that enhance hepcidin transcription in hepatocytes[20]. Specifically, the iron-bound transferrin-TfR2-HFE complex mediates conformational changes that activate downstream signaling, ensuring that increased iron availability triggers increased hepcidin production to limit further iron absorption[20].

Importantly, disruption of the HFE-TfR1 interaction alone does not impair hepcidin regulation, suggesting that HFE sequestration from TfR1 allows its interaction with TfR2, which appears to be the critical complex for hepcidin regulation[20]. This model proposes that TfR1 competes with TfR2 for HFE binding under low holo-transferrin conditions, but when iron-loaded transferrin concentrations increase, the holo-transferrin-TfR2-HFE complex forms and activates hepcidin transcription[20]. Evidence supporting this model includes observations that in TfR1 mutant mice lacking functional TfR1, higher levels of hepcidin mRNA accumulate, consistent with increased availability of HFE to bind TfR2[20]. This elegant regulatory mechanism demonstrates how TfR1's role extends beyond simple iron uptake to encompass systemic iron homeostasis through protein-protein interactions controlling hormonal signaling[20].

Ferritin Binding and Alternative Iron Acquisition Pathways

Beyond transferrin, TfR1 binds heavy-chain ferritin (H-Ft), providing an alternative source of bioavailable iron for cells[19][22]. Ferritin, a spherical 24-subunit iron storage protein composed of heavy-chain (FHC) and light-chain (FLC) subunits, circulates in plasma at low concentrations and can be internalized by cells expressing TfR1[19][22]. The binding of ferritin to TfR1 occurs through distinct epitopes compared to those used for transferrin binding, with structural studies revealing that specific residues in the ferritin BC-loop (particularly Y211 and N-terminal residues of the A helix including Q14, D15, and R22) are critical for receptor recognition[22]. Notably, ferritin composed entirely of light chains does not bind TfR1, indicating that heavy-chain subunits provide the essential binding determinants[19][22]. Upon binding and internalization through TfR1-mediated endocytosis, ferritin enters both endosomal and lysosomal compartments where acidification and proteolysis release stored iron[19].

The functional significance of ferritin-TfR1 interaction becomes particularly apparent in erythroid precursors, where ferritin uptake via TfR1 can provide sufficient iron for hemoglobin synthesis in the absence of transferrin, demonstrating functional redundancy in iron acquisition pathways[19]. This dual-receptor function suggests that ferritin and transferrin may serve complementary roles in coordinating iron processing and utilization, potentially allowing cells to respond flexibly to varying iron bioavailability in different physiological contexts[19][22]. The shared use of TfR1 for both transferrin and ferritin uptake raises interesting questions about how endosomal iron metabolism differs between these two pathways and whether ferritin-derived iron might supply specific pools of iron within the cell[19].

Cellular and Tissue Distribution

Expression Patterns in Normal Tissues and Cell Types

TfR1 exhibits a remarkably broad tissue distribution, reflecting the fundamental importance of iron for virtually all nucleated cells[13][16]. Expression is particularly abundant in tissues with high metabolic rates or rapid cell proliferation, including bone marrow, placenta, and rapidly proliferating epithelial tissues[13][16]. Within normal bone marrow, TfR1 is expressed predominantly on erythroid precursor cells of all maturation stages, with expression being essentially absent from mature erythrocytes[1][2][40]. This developmental pattern of expression makes physiological sense, as mature red blood cells have lost their nuclei and cannot synthesize new hemoglobin, eliminating their requirement for iron import[40]. In contrast, erythroid precursor cells express extremely high levels of TfR1 to satisfy the enormous iron demands of hemoglobin synthesis, with approximately 80% of total cellular iron utilization occurring in erythroid precursors for hemoglobin production, and consequently, approximately 80% of total TfR1 is expressed on erythroid cells[15][40].

Beyond erythropoiesis, TfR1 is expressed on hepatocytes, Kupffer cells (tissue macrophages of the liver), endocrine pancreas cells, basal epidermis, testicular tissue, and pituitary cells in normal tissues[13]. This distribution reflects the iron requirements of different cell types for essential enzymatic functions and metabolic processes[13]. The restricted pattern of expression in normal tissues contrasts sharply with its widespread upregulation in malignant neoplasms, where rapidly dividing cancer cells dramatically increase TfR1 expression to meet escalated iron demands for ribonucleotide reductase and other iron-dependent biosynthetic enzymes required for DNA synthesis and cell proliferation[13][39].

Expression in Erythropoiesis and Hemoglobin Synthesis

Erythropoiesis represents the physiological context in which TfR1 achieves its highest expression levels and most critical functional importance[40]. During differentiation of erythroid progenitors stimulated by erythropoietin (EPO), cells progressively increase TfR1 surface levels, enabling them to import the massive quantities of iron required for hemoglobin synthesis[40]. The process of hemoglobin production demands approximately 30 million iron atoms per second in an adult human, highlighting the extraordinary iron-handling capacity that must be maintained by the erythroid compartment[40]. Recent discoveries have identified Grab, a guanine nucleotide exchange factor for Rab8, as a critical erythroid-specific regulator of TfR1 recycling to the plasma membrane[37]. Polymorphisms in GRAB and RAB8 genes associate with variations in mean corpuscular hemoglobinization of red blood cells, indicating that genetic variation in recycling machinery influences iron delivery efficiency and ultimately hemoglobin accumulation[37].

The Grab-Rab8 axis appears to function by recruiting the exocyst to recycling endosomes in an iron-demand-responsive manner, controlling the rate at which TfR1 is returned to the plasma membrane to import additional iron[37]. In Grab-deficient cells, TfR1 fails to recycle efficiently, accumulating in intracellular compartments and eventually being diverted to lysosomes for degradation, resulting in decreased cellular iron uptake and reduced hemoglobin synthesis[37]. These findings suggest that erythroid-specific recycling machinery provides a regulatory point for modulating iron uptake capacity in response to the differentiation stage and hemoglobin synthesis requirements of developing red blood cells[37].

Specialized Functions and Pathological Roles

Blood-Brain Barrier Transcytosis and Central Nervous System Iron Delivery

The blood-brain barrier (BBB) presents a formidable obstacle to drug delivery to the central nervous system, restricting passage of most large molecules and permitting only small, lipophilic compounds to cross the endothelial monolayer forming this barrier[24]. However, TfR1 is highly expressed on brain endothelial cells of the BBB, where it mediates transcytosis of transferrin-bound iron from systemic circulation into brain parenchyma, delivering this essential nutrient across an otherwise impermeable barrier[24]. Antibodies targeting TfR1, particularly anti-TfR1 monoclonal antibodies, have been engineered to exploit this physiological transcytotic pathway for drug delivery, with the antibodies being internalized at the luminal surface of brain endothelial cells and transcytosed to the abluminal surface, delivering attached therapeutic cargo to brain tissues[21][24].

The efficiency of transcytosis appears critically dependent on the binding affinity of anti-TfR1 antibodies to their epitope[21]. Paradoxically, high-affinity antibodies demonstrate reduced transcytosis efficiency, with antibodies showing affinities of 76 nanoMolar and 108 nanoMolar transporting more efficiently across the BBB than high-affinity 5 nanoMolar variants[21]. The mechanistic explanation for this counterintuitive finding involves antibody sorting and trafficking within endosomal compartments—high-affinity bivalent antibodies are preferentially directed toward late endosomes and lysosomes for degradation, whereas lower-affinity variants are preferentially sorted toward early endosomes, from which they can be efficiently recycled and exocytosed on the abluminal surface[21]. This sorting mechanism appears linked to alterations in endocytic recycling pathways triggered by different avidity states of antibody-receptor interactions, with monovalent antibodies showing particular efficiency in promoting transcytosis by favoring early endosomal sorting tubules[21].

Role in Cancer Cell Proliferation and Metabolic Support

TfR1 is dramatically overexpressed on the surfaces of malignant cells from multiple cancer types, including breast cancer, gliomas, ovarian cancer, lung cancer, hepatocellular carcinoma, and colon cancer, establishing it as a universal cancer biomarker[39][42]. Cancer cells upregulate TfR1 expression to meet escalated iron demands driven by rapid proliferation requiring DNA synthesis, the rate-limiting step of which depends on ribonucleotide reductase (RNR)—an iron-dependent enzyme synthesizing nucleotide precursors[39][42]. Iron serves as an essential cofactor for the R1 subunit of ribonucleotide reductase, which forms a critical tyrosyl radical on Tyr122 required for catalytic activity[39]. Additionally, iron-dependent proteins including electron transport chain components become increasingly critical in cancer cells supporting altered metabolic states, making iron availability a potential therapeutic vulnerability[42].

Studies demonstrating blocking of anti-TfR1 monoclonal antibodies inhibit cancer cell proliferation through iron deprivation represent proof-of-concept for TfR1-targeted therapeutic approaches[42]. Notably, anti-TfR1 antibodies inhibit growth of erythroleukemia and B-cell lymphoma cell lines with IC50 values as low as 0.1 micrograms per milliliter, with in vivo studies showing tumor regression in xenograft models through mechanisms involving both iron deprivation and antibody-dependent cellular cytotoxic effector functions[51]. Importantly, anti-TfR1 treatment additionally upregulates hypoxia-inducible factor-1 alpha (HIF-1α) through reduced iron availability for prolyl hydroxylase activity, potentially increasing tumor angiogenesis, suggesting that optimal therapeutic strategies might combine anti-TfR1 antibodies with agents targeting hypoxia pathways[42].

Recent evidence indicates that TfR1 expression correlates with poor overall survival in osteosarcoma patients, with TFRC knockdown in osteosarcoma cell lines significantly reducing proliferation, migration, and invasion abilities[39]. The mechanism involves decreased total intracellular iron content following TFRC knockdown, leading to reduced ribonucleotide reductase 2 (RRM2) expression and activity[39]. Remarkably, the reduction in osteosarcoma cell proliferation caused by TFRC knockdown can be reversed by supplementing cells with ferric ammonium citrate (FAC) or by overexpressing RRM2, directly demonstrating that TFRC-mediated iron uptake drives RRM2-dependent DNA synthesis supporting cancer cell proliferation[39].

Viral Exploitation of Transferrin Receptor for Cell Entry

Multiple viral pathogens have evolved to exploit TfR1 as a cellular entry receptor, exploiting the abundance of this protein on target cells and its constitutive endocytic trafficking to acidic compartments favorable for viral membrane fusion[50][53]. New World arenaviruses causing hemorrhagic fevers in humans—including Machupo, Guanarito, Junin, and Sabia viruses—utilize human TfR1 as their cellular receptor, with the viral entry glycoprotein (GP) binding directly and specifically to TfR1[53]. Expression of human TfR1 in hamster cell lines markedly enhances infection by pseudoviruses displaying New World arenavirus GPs, whereas cells lacking TfR1 show minimal infection[53]. Conversely, Old World arenaviruses such as Lassa virus do not utilize TfR1 but instead use α-dystroglycan as a cellular receptor, demonstrating specific viral adaptation to particular receptor systems[53].

The structural basis for TfR1-viral GP interaction involves specific epitopes on TfR1 that are recognized by viral glycoproteins with high affinity comparable to transferrin binding[53]. Critically, anti-TfR1 monoclonal antibodies efficiently inhibit replication of Machupo, Guanarito, Junin, and Sabia viruses but not Lassa virus, demonstrating the functional requirement for TfR1 in New World arenavirus infection[53]. Remarkably, iron status influences viral infection efficiency, with iron depletion enhancing infection of Junin and Machupo pseudoviruses but not affecting Lassa virus, suggesting that iron-dependent conformational changes of TfR1 may enhance viral GP binding[53]. This viral dependence on TfR1 reflects both the abundance of this receptor on target cells and the evolutionary optimization of viral entry mechanisms to exploit constitutive endocytic pathways that deliver viral particles to appropriate intracellular compartments for membrane fusion[50][53].

Role in Immune Dysfunction and Autoimmune Disease

Emerging research reveals that TfR1-mediated iron uptake plays unexpected roles in immune cell dysfunction and autoimmune diseases. In systemic lupus erythematosus (SLE), a prototypic autoimmune disease characterized by dysfunctional T cells, recent CRISPR screening identified TfR1 (CD71) as a critical factor specifically critical for T helper 17 cell (TH17) differentiation and inhibitory for induced regulatory T cells (iTregs)[54]. SLE-prone T cells display enhanced CD71 expression resulting from altered endosomal recycling, leading to increased intracellular iron accumulation[54]. This elevated iron uptake impairs mitochondrial function and mTORC1 signaling, skewing T cell differentiation toward pro-inflammatory TH17 and away from immunosuppressive iTregs[54]. Remarkably, anti-CD71 treatment reduces intracellular iron, inhibits TH17 differentiation, promotes IL-10 production by CD4 T cells, and reverses disease manifestations in SLE-prone mice[54]. Disease severity in SLE patients correlates directly with CD71 expression on TH17 cells, highlighting the pathogenic role of iron metabolism dysregulation in autoimmune dysfunction[54].

Clinical Applications and Diagnostic Utility

Soluble Transferrin Receptor as a Biomarker

TfR1 undergoes proteolytic cleavage at an Arg-Leu bond distal to the second disulfide bond linking the two monomers, releasing the soluble form of transferrin receptor (sTfR), a truncated protein lacking the transmembrane domain and consisting of 660 amino acids comprising the ectodomain[15][18]. This soluble form circulates in plasma at concentrations proportional to total cellular TfR1 abundance, making sTfR a valuable biomarker for iron metabolism status[15][18]. Approximately 80% of metabolic iron is incorporated into hemoglobin by erythroid precursors, and since most cellular TfR1 resides on erythroid cells, circulating sTfR concentration reflects erythroid precursor mass and erythropoiesis rate[15][40].

Circulating sTfR is particularly clinically useful for distinguishing iron deficiency from other causes of anemia or elevated ferritin levels[18]. Unlike ferritin, which functions as an acute-phase reactant elevated during inflammation, infection, malignancy, and chronic disease without indicating iron deficiency, sTfR is not influenced by inflammatory states[18]. Patients with iron deficiency show elevated sTfR levels as their erythroid precursor cells upregulate TfR1 to maximize iron capture from limited iron availability[18]. In contrast, patients with hypoplastic anemias (reduced erythropoiesis due to bone marrow failure) show low sTfR levels despite potentially low iron, allowing discrimination between iron deficiency and bone marrow failure[18]. Additionally, sTfR has been employed as a marker for erythropoietin (EPO) misuse by athletes, as EPO administration increases erythropoiesis and consequently sTfR levels, providing a physiological indicator of illicit EPO injection[4].

Immunohistochemical Applications

CD71 (TfR1) serves as a robust immunohistochemical marker for several tissue types and disease processes. In particular, CD71 is highly expressed on chorionic villous trophoblasts of the placenta, with CD71 immunostaining particularly useful for identifying villous structures in necrotic or autolytic specimens where other morphologic features become obscured[1][13]. Among hematopoietic cells, CD71 is expressed specifically by erythroid precursors within the normal bone marrow and spleen, with this restricted expression pattern allowing discrimination of erythroid lineage cells from other hematopoietic populations[1][2]. In combination with markers specific to more mature erythrocytes such as glycophorin A (recognized by the TER-119 antibody in mice), flow cytometry analysis can track erythroid differentiation and assess changes in erythropoiesis during disease or treatment[2]. The CD71-positive population in bone marrow encompasses early erythroid precursors (proerythroblasts and early normoblasts) that actively synthesize hemoglobin, providing a specific identification of erythropoietic activity[2].

Therapeutic Targeting and Drug Development

The prominent role of TfR1 in iron-dependent proliferation of cancer cells and its use by pathogenic viruses has spurred substantial drug development efforts targeting this receptor. Anti-TfR1 monoclonal antibodies represent the most advanced class of TfR1-targeting therapeutics, with multiple antibody formats being evaluated in clinical trials[51]. These antibodies block transferrin binding to TfR1, preventing iron-loaded transferrin internalization and causing iron starvation in target cells. Some anti-TfR1 antibodies show rapid internalization upon binding, making them suitable for delivery of attached therapeutic cargos into cells[51]. This property has enabled development of anti-TfR1 antibody-drug conjugates and fusion proteins combining anti-TfR1 antibodies with toxins, enzymes, or other therapeutic agents, allowing selective drug delivery to TfR1-expressing cancer cells[51].

InatherYs (now part of the InatherYs group), a biotechnology company in Évry, France, developed INA01, an anti-CD71 antibody candidate demonstrating efficacy in preclinical studies for treating two incurable orphan hematologic malignancies—adult T cell leukemia (ATLL) caused by human T-lymphotropic virus-1 (HTLV-1) infection and mantle cell lymphoma (MCL)[1]. These findings suggest that TfR1-targeted approaches may prove particularly valuable for treating malignancies in which TfR1 is particularly highly expressed or functionally critical for survival. Additionally, researchers have exploited the TfR1 transcytosis pathway at the blood-brain barrier for delivery of anti-TfR1 antibody fusion proteins carrying therapeutic cargos to brain tissues, enabling treatment of central nervous system diseases including glioblastoma and other CNS malignancies[24][51].

Evolutionary Conservation and Comparative Biology

Structural Homology and Family Relationships

TfR1 belongs to the M28 family of zinc-dependent peptidases and shares structural homology with numerous peptidase family members, including glutamate carboxypeptidase II (GCP2, also called PSMA), N-acetylated alpha-linked acidic dipeptidase (NAALAD), and related proteins[45][49]. Despite this structural similarity to catalytically active peptidases, TfR1 itself is catalytically inactive, having diverged from peptidase family members through loss of critical catalytic residues while retaining the overall structural scaffold[43]. This apparent evolutionary conversion of an active peptidase domain into a ligand-binding domain demonstrates how evolution repurposes protein domains for novel functions while maintaining structural integrity[49]. The transfer receptor family in primates is represented by at least seven different homologous proteins, indicating repeated gene duplication events in vertebrate evolution, likely reflecting divergent specialization of these receptors for distinct biological roles[45].

Positive Selection and Species-Specific Adaptations

Comparative genomic analyses have revealed evidence for positive selection acting on the TFRC gene during the evolution of Caniformia (the clade including dogs and their relatives), suggesting that specific amino acid changes in TfR1 confer adaptive advantages in these species[48]. This evolutionary signature of positive selection on a receptor gene is relatively uncommon and suggests that changes in iron metabolism or iron sensing may have provided fitness advantages during caniform evolution, perhaps related to changes in dietary iron sources or metabolic rates[48]. Such evolutionary adaptation at TfR1 demonstrates that the specific sequence of this iron transport protein is subject to selective constraints and that functional optimization of TfR1 for each species' particular physiological requirements drives amino acid evolution[48].

Conclusions and Future Perspectives

Transferrin receptor protein 1 represents one of the most comprehensively characterized iron transport proteins, reflecting both its fundamental biological importance and its prominence as a therapeutic target. The sophisticated molecular mechanisms governing TfR1 function—including pH-sensitive binding to transferrin with active promotion of iron release, rapid endocytic internalization through clathrin-dependent pathways, highly regulated recycling through Rab-mediated trafficking, and post-transcriptional control through iron-responsive elements—demonstrate the cellular investment in ensuring appropriate iron delivery matched to cellular needs. The protein's participation in diverse biological processes ranging from hemoglobin synthesis in erythroid precursors to iron sensing controlling systemic hepcidin production illustrates how a single receptor integrates multiple physiological signals to coordinate iron metabolism at cellular and organismal levels.

The emerging recognition of TfR1's roles beyond basic iron transport—including its function as a regulator of alternative splicing patterns, its involvement in viral cell entry, and its pathogenic role in autoimmune diseases—suggests that our understanding of this protein's biology remains incomplete. Future research employing structural biology, single-molecule studies, and system-wide approaches will likely reveal additional regulatory mechanisms and biological contexts in which TfR1 participates. The therapeutic potential of targeting TfR1 in cancer, leveraging the protein's abundant expression on rapidly dividing cells and the critical importance of iron for DNA synthesis, continues to drive drug development efforts that may provide effective treatments for otherwise intractable malignancies. As research deepens understanding of TfR1 biology and function, this protein will undoubtedly continue serving as a paradigm for understanding how cells precisely regulate nutrient acquisition in response to metabolic demands and environmental iron availability.

Citations

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📄 View Raw YAML

id: P02786
gene_symbol: TFRC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'TODO: Add description for TFRC'
existing_annotations:
  - term:
      id: GO:0006826
      label: iron ion transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: file:human/TFRC/TFRC-deep-research-perplexity.md
          supporting_text: See deep research file for comprehensive analysis
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0009897
      label: external side of plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0046718
      label: symbiont entry into host cell
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0001618
      label: virus receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0004998
      label: transferrin receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0006897
      label: endocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0033572
      label: transferrin transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0042470
      label: melanosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0060586
      label: multicellular organismal-level iron ion homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0001666
      label: response to hypoxia
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005769
      label: early endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005905
      label: clathrin-coated pit
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0006953
      label: acute-phase response
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0007584
      label: response to nutrient
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0009897
      label: external side of plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0010039
      label: response to iron ion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0010042
      label: response to manganese ion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030316
      label: osteoclast differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030544
      label: Hsp70 protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0032526
      label: response to retinoic acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0046688
      label: response to copper ion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0051087
      label: protein-folding chaperone binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0055037
      label: recycling endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0055038
      label: recycling endosome membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0098794
      label: postsynapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0098944
      label: postsynaptic recycling endosome membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0099072
      label: regulation of postsynaptic membrane neurotransmitter receptor 
        levels
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:1990712
      label: HFE-transferrin receptor complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14691533
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:14691533
          supporting_text: Mechanism for multiple ligand recognition by the 
            human transferrin receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15965644
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:15965644
          supporting_text: Jun 18. The Q283P amino-acid change in HFE leads to 
            structural and functional consequences similar to those described 
            for the mutated 282Y HFE protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16271884
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16271884
          supporting_text: The molecular mechanism for receptor-stimulated iron 
            release from the plasma iron transport protein transferrin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16325581
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16325581
          supporting_text: TTP specifically regulates the internalization of the
            transferrin receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16354665
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16354665
          supporting_text: 2005 Dec 14. Release of the soluble transferrin 
            receptor is directly regulated by binding of its ligand 
            ferritransferrin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20133674
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20133674
          supporting_text: Binding and uptake of H-ferritin are mediated by 
            human transferrin receptor-1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20404192
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20404192
          supporting_text: Noncanonical interactions between serum transferrin 
            and transferrin receptor evaluated with electrospray ionization mass
            spectrometry.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20618438
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20618438
          supporting_text: 2010 Jul 5. N-glycosylation is important for the 
            correct intracellular localization of HFE and its ability to 
            decrease cell surface transferrin binding.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21788477
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:21788477
          supporting_text: How the binding of human transferrin primes the 
            transferrin receptor potentiating iron release at endosomal pH.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23384347
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23384347
          supporting_text: The transferrin receptor-1 membrane stub undergoes 
            intramembrane proteolysis by signal peptide peptidase-like 2b.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29302006
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:29302006
          supporting_text: Transferrin receptor 1 is a reticulocyte-specific 
            receptor for Plasmodium vivax.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29950717
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:29950717
          supporting_text: Jun 27. Cryo-EM structure of an essential Plasmodium 
            vivax invasion complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein 
            interactome.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:20208545
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20208545
          supporting_text: Mar 7. Structural basis for receptor recognition by 
            New World hemorrhagic fever arenaviruses.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23384347
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23384347
          supporting_text: The transferrin receptor-1 membrane stub undergoes 
            intramembrane proteolysis by signal peptide peptidase-like 2b.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:29302006
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:29302006
          supporting_text: Transferrin receptor 1 is a reticulocyte-specific 
            receptor for Plasmodium vivax.
  - term:
      id: GO:0004998
      label: transferrin receptor activity
    evidence_type: IDA
    original_reference_id: PMID:9465039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9465039
          supporting_text: The hemochromatosis gene product complexes with the 
            transferrin receptor and lowers its affinity for ligand binding.
  - term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    evidence_type: IDA
    original_reference_id: PMID:9465039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9465039
          supporting_text: The hemochromatosis gene product complexes with the 
            transferrin receptor and lowers its affinity for ligand binding.
  - term:
      id: GO:0007166
      label: cell surface receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:9465039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9465039
          supporting_text: The hemochromatosis gene product complexes with the 
            transferrin receptor and lowers its affinity for ligand binding.
  - term:
      id: GO:0033572
      label: transferrin transport
    evidence_type: IDA
    original_reference_id: PMID:9465039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9465039
          supporting_text: The hemochromatosis gene product complexes with the 
            transferrin receptor and lowers its affinity for ligand binding.
  - term:
      id: GO:0004998
      label: transferrin receptor activity
    evidence_type: IDA
    original_reference_id: PMID:18353247
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18353247
          supporting_text: Epub 2008 Mar 7. HFE association with transferrin 
            receptor 2 increases cellular uptake of transferrin-bound iron.
  - term:
      id: GO:0033572
      label: transferrin transport
    evidence_type: IDA
    original_reference_id: PMID:18353247
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18353247
          supporting_text: Epub 2008 Mar 7. HFE association with transferrin 
            receptor 2 increases cellular uptake of transferrin-bound iron.
  - term:
      id: GO:0005764
      label: lysosome
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:38625739
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:38625739
          supporting_text: The secreted micropeptide C4orf48 enhances renal 
            fibrosis via an RNA-binding mechanism.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0004998
      label: transferrin receptor activity
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0060586
      label: multicellular organismal-level iron ion homeostasis
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5691154
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8866277
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867754
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867756
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868071
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868072
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868230
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868236
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868648
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868651
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868661
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917807
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917814
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917839
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917987
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:23137377
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23137377
          supporting_text: 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.
  - term:
      id: GO:0150104
      label: transport across blood-brain barrier
    evidence_type: NAS
    original_reference_id: PMID:30280653
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:30280653
          supporting_text: 'Blood-Brain Barrier: From Physiology to Disease and Back.'
  - term:
      id: GO:0010637
      label: negative regulation of mitochondrial fusion
    evidence_type: IMP
    original_reference_id: PMID:26214738
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26214738
          supporting_text: Regulation of mitochondrial morphology and function 
            by stearoylation of TFR1.
  - term:
      id: GO:0035556
      label: intracellular signal transduction
    evidence_type: IMP
    original_reference_id: PMID:26214738
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26214738
          supporting_text: Regulation of mitochondrial morphology and function 
            by stearoylation of TFR1.
  - term:
      id: GO:0150104
      label: transport across blood-brain barrier
    evidence_type: NAS
    original_reference_id: PMID:26590417
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26590417
          supporting_text: Establishment and Dysfunction of the Blood-Brain 
            Barrier.
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:1900182
      label: positive regulation of protein localization to nucleus
    evidence_type: IMP
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0031334
      label: positive regulation of protein-containing complex assembly
    evidence_type: IMP
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    evidence_type: IMP
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0044877
      label: protein-containing complex binding
    evidence_type: IPI
    original_reference_id: PMID:23016877
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23016877
          supporting_text: TfR1 interacts with the IKK complex and is involved 
            in IKK-NF-κB signalling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29388418
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:29388418
          supporting_text: Epub 2018 Feb 12. Transferrin Receptors TfR1 and TfR2
            Bind Transferrin through Differing Mechanisms.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: ISS
    original_reference_id: PMID:18619525
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18619525
          supporting_text: Subcellular localization of transporters along the 
            rat blood-brain barrier and blood-cerebral-spinal fluid barrier by 
            in vivo biotinylation.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868658
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868659
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868660
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868661
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8869438
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871193
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871194
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917807
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917814
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917835
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: IDA
    original_reference_id: PMID:16380373
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16380373
          supporting_text: 2005 Dec 27. Sec14 homology domain targets p50RhoGAP 
            to endosomes and provides a link between Rab and Rho GTPases.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:16380373
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16380373
          supporting_text: 2005 Dec 27. Sec14 homology domain targets p50RhoGAP 
            to endosomes and provides a link between Rab and Rho GTPases.
  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IDA
    original_reference_id: PMID:15229288
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:15229288
          supporting_text: 2004 Jun 30. Over-expression of Rififylin, a new RING
            finger and FYVE-like domain-containing protein, inhibits recycling 
            from the endocytic recycling compartment.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0030890
      label: positive regulation of B cell proliferation
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0042102
      label: positive regulation of T cell proliferation
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0045830
      label: positive regulation of isotype switching
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0031623
      label: receptor internalization
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0033572
      label: transferrin transport
    evidence_type: IDA
    original_reference_id: PMID:26642240
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26642240
          supporting_text: A missense mutation in TFRC, encoding transferrin 
            receptor 1, causes combined immunodeficiency.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9990067
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9990067
          supporting_text: Association of HFE protein with transferrin receptor 
            in crypt enterocytes of human duodenum.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:9990067
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9990067
          supporting_text: Association of HFE protein with transferrin receptor 
            in crypt enterocytes of human duodenum.
  - term:
      id: GO:1990712
      label: HFE-transferrin receptor complex
    evidence_type: IDA
    original_reference_id: PMID:9990067
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9990067
          supporting_text: Association of HFE protein with transferrin receptor 
            in crypt enterocytes of human duodenum.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18353247
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18353247
          supporting_text: Epub 2008 Mar 7. HFE association with transferrin 
            receptor 2 increases cellular uptake of transferrin-bound iron.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IGI
    original_reference_id: PMID:18353247
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18353247
          supporting_text: Epub 2008 Mar 7. HFE association with transferrin 
            receptor 2 increases cellular uptake of transferrin-bound iron.
  - term:
      id: GO:0009897
      label: external side of plasma membrane
    evidence_type: IGI
    original_reference_id: PMID:18353247
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18353247
          supporting_text: Epub 2008 Mar 7. HFE association with transferrin 
            receptor 2 increases cellular uptake of transferrin-bound iron.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9546397
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9546397
          supporting_text: Crystal structure of the hemochromatosis protein HFE 
            and characterization of its interaction with transferrin receptor.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IPI
    original_reference_id: PMID:9546397
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9546397
          supporting_text: Crystal structure of the hemochromatosis protein HFE 
            and characterization of its interaction with transferrin receptor.
  - term:
      id: GO:1990712
      label: HFE-transferrin receptor complex
    evidence_type: IDA
    original_reference_id: PMID:9546397
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9546397
          supporting_text: Crystal structure of the hemochromatosis protein HFE 
            and characterization of its interaction with transferrin receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9465039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9465039
          supporting_text: The hemochromatosis gene product complexes with the 
            transferrin receptor and lowers its affinity for ligand binding.
  - term:
      id: GO:1990712
      label: HFE-transferrin receptor complex
    evidence_type: IDA
    original_reference_id: PMID:9465039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:9465039
          supporting_text: The hemochromatosis gene product complexes with the 
            transferrin receptor and lowers its affinity for ligand binding.
  - term:
      id: GO:1903561
      label: extracellular vesicle
    evidence_type: HDA
    original_reference_id: PMID:24769233
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:24769233
          supporting_text: '2014 Apr 24. Proteomic analysis of cerebrospinal fluid
            extracellular vesicles: a comprehensive dataset.'
  - term:
      id: GO:0071466
      label: cellular response to xenobiotic stimulus
    evidence_type: IDA
    original_reference_id: PMID:16254249
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16254249
          supporting_text: Assigning functions to distinct regions of the 
            N-terminus of the prion protein that are involved in its 
            copper-stimulated, clathrin-dependent endocytosis.
  - term:
      id: GO:0055037
      label: recycling endosome
    evidence_type: IDA
    original_reference_id: PMID:24561039
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:24561039
          supporting_text: 2014 Feb 20. Rab11 endosomes contribute to mitotic 
            spindle organization and orientation.
  - term:
      id: GO:0055037
      label: recycling endosome
    evidence_type: IDA
    original_reference_id: PMID:22456507
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22456507
          supporting_text: 2012 Mar 28. Dynamic and transient interactions of 
            Atg9 with autophagosomes, but not membrane integration, are required
            for autophagy.
  - term:
      id: GO:0001558
      label: regulation of cell growth
    evidence_type: IMP
    original_reference_id: PMID:7556058
    negated: true
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7556058
          supporting_text: A novel iron uptake mechanism mediated by 
            GPI-anchored human p97.
  - term:
      id: GO:0006826
      label: iron ion transport
    evidence_type: IDA
    original_reference_id: PMID:7556058
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7556058
          supporting_text: A novel iron uptake mechanism mediated by 
            GPI-anchored human p97.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IDA
    original_reference_id: PMID:7556058
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7556058
          supporting_text: A novel iron uptake mechanism mediated by 
            GPI-anchored human p97.
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:7556058
    negated: true
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7556058
          supporting_text: A novel iron uptake mechanism mediated by 
            GPI-anchored human p97.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22658674
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22658674
          supporting_text: May 31. Insights into RNA biology from an atlas of 
            mammalian mRNA-binding proteins.
  - term:
      id: GO:0072562
      label: blood microparticle
    evidence_type: HDA
    original_reference_id: PMID:22516433
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22516433
          supporting_text: Epub 2012 Apr 10. Proteomic analysis of microvesicles
            from plasma of healthy donors reveals high individual variability.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: HDA
    original_reference_id: PMID:22664934
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22664934
          supporting_text: Comparison of tear protein levels in breast cancer 
            patients and healthy controls using a de novo proteomic approach.
  - term:
      id: GO:0003725
      label: double-stranded RNA binding
    evidence_type: IDA
    original_reference_id: PMID:21266579
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:21266579
          supporting_text: 2011 Jan 25. Raftlin is involved in the nucleocapture
            complex to induce poly(I:C)-mediated TLR3 activation.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in 
            B-cell exosomes and potential functional implications for exosome 
            biogenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10638746
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:10638746
          supporting_text: Crystal structure of the hereditary haemochromatosis 
            protein HFE complexed with transferrin receptor.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:20202662
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20202662
          supporting_text: 2010 Mar 3. Ebola virus uses clathrin-mediated 
            endocytosis as an entry pathway.
  - term:
      id: GO:0005905
      label: clathrin-coated pit
    evidence_type: IDA
    original_reference_id: PMID:12857860
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:12857860
          supporting_text: Mar 20. Myo6 facilitates the translocation of 
            endocytic vesicles from cell peripheries.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: PMID:14612438
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:14612438
          supporting_text: Nov 11. Zn2+-stimulated endocytosis of the mZIP4 zinc
            transporter regulates its location at the plasma membrane.
  - term:
      id: GO:0004998
      label: transferrin receptor activity
    evidence_type: TAS
    original_reference_id: PMID:10192390
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:10192390
          supporting_text: Transferrin receptor is necessary for development of 
            erythrocytes and the nervous system.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: TAS
    original_reference_id: PMID:8394993
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:8394993
          supporting_text: Differential effects of antimycin A on endocytosis 
            and exocytosis of transferrin also are observed for internalization 
            and externalization of beta-adrenergic receptors.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:6090955
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:6090955
          supporting_text: Primary structure of human transferrin receptor 
            deduced from the mRNA sequence.
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: TAS
    original_reference_id: PMID:10192390
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:10192390
          supporting_text: Transferrin receptor is necessary for development of 
            erythrocytes and the nervous system.
  - term:
      id: GO:0004998
      label: transferrin receptor activity
    evidence_type: NAS
    original_reference_id: PMID:1871153
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:1871153
          supporting_text: Characterization of transferrin receptor released by 
            K562 erythroleukemia cells.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IDA
    original_reference_id: PMID:1871153
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:1871153
          supporting_text: Characterization of transferrin receptor released by 
            K562 erythroleukemia cells.
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: NAS
    original_reference_id: PMID:1871153
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:1871153
          supporting_text: Characterization of transferrin receptor released by 
            K562 erythroleukemia cells.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: NAS
    original_reference_id: PMID:1871153
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:1871153
          supporting_text: Characterization of transferrin receptor released by 
            K562 erythroleukemia cells.
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt.
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara.
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links.
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:10192390
    title: Transferrin receptor is necessary for development of erythrocytes and
      the nervous system.
    findings: []
  - id: PMID:10638746
    title: Crystal structure of the hereditary haemochromatosis protein HFE 
      complexed with transferrin receptor.
    findings: []
  - id: PMID:12857860
    title: Myo6 facilitates the translocation of endocytic vesicles from cell 
      peripheries.
    findings: []
  - id: PMID:14612438
    title: Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates 
      its location at the plasma membrane.
    findings: []
  - id: PMID:14691533
    title: Mechanism for multiple ligand recognition by the human transferrin 
      receptor.
    findings: []
  - id: PMID:15229288
    title: Over-expression of Rififylin, a new RING finger and FYVE-like 
      domain-containing protein, inhibits recycling from the endocytic recycling
      compartment.
    findings: []
  - id: PMID:15965644
    title: The Q283P amino-acid change in HFE leads to structural and functional
      consequences similar to those described for the mutated 282Y HFE protein.
    findings: []
  - id: PMID:16254249
    title: Assigning functions to distinct regions of the N-terminus of the 
      prion protein that are involved in its copper-stimulated, 
      clathrin-dependent endocytosis.
    findings: []
  - id: PMID:16271884
    title: The molecular mechanism for receptor-stimulated iron release from the
      plasma iron transport protein transferrin.
    findings: []
  - id: PMID:16325581
    title: TTP specifically regulates the internalization of the transferrin 
      receptor.
    findings: []
  - id: PMID:16354665
    title: Release of the soluble transferrin receptor is directly regulated by 
      binding of its ligand ferritransferrin.
    findings: []
  - id: PMID:16380373
    title: Sec14 homology domain targets p50RhoGAP to endosomes and provides a 
      link between Rab and Rho GTPases.
    findings: []
  - id: PMID:18353247
    title: HFE association with transferrin receptor 2 increases cellular uptake
      of transferrin-bound iron.
    findings: []
  - id: PMID:18619525
    title: Subcellular localization of transporters along the rat blood-brain 
      barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation.
    findings: []
  - id: PMID:1871153
    title: Characterization of transferrin receptor released by K562 
      erythroleukemia cells.
    findings: []
  - id: PMID:20133674
    title: Binding and uptake of H-ferritin are mediated by human transferrin 
      receptor-1.
    findings: []
  - id: PMID:20202662
    title: Ebola virus uses clathrin-mediated endocytosis as an entry pathway.
    findings: []
  - id: PMID:20208545
    title: Structural basis for receptor recognition by New World hemorrhagic 
      fever arenaviruses.
    findings: []
  - id: PMID:20404192
    title: Noncanonical interactions between serum transferrin and transferrin 
      receptor evaluated with electrospray ionization mass spectrometry.
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes and potential 
      functional implications for exosome biogenesis.
    findings: []
  - id: PMID:20618438
    title: N-glycosylation is important for the correct intracellular 
      localization of HFE and its ability to decrease cell surface transferrin 
      binding.
    findings: []
  - id: PMID:21266579
    title: Raftlin is involved in the nucleocapture complex to induce 
      poly(I:C)-mediated TLR3 activation.
    findings: []
  - id: PMID:21788477
    title: How the binding of human transferrin primes the transferrin receptor 
      potentiating iron release at endosomal pH.
    findings: []
  - id: PMID:22456507
    title: Dynamic and transient interactions of Atg9 with autophagosomes, but 
      not membrane integration, are required for autophagy.
    findings: []
  - id: PMID:22516433
    title: Proteomic analysis of microvesicles from plasma of healthy donors 
      reveals high individual variability.
    findings: []
  - id: PMID:22658674
    title: Insights into RNA biology from an atlas of mammalian mRNA-binding 
      proteins.
    findings: []
  - id: PMID:22664934
    title: Comparison of tear protein levels in breast cancer patients and 
      healthy controls using a de novo proteomic approach.
    findings: []
  - id: PMID:23016877
    title: "TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling."
    findings: []
  - id: PMID:23137377
    title: 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.
    findings: []
  - id: PMID:23384347
    title: The transferrin receptor-1 membrane stub undergoes intramembrane 
      proteolysis by signal peptide peptidase-like 2b.
    findings: []
  - id: PMID:24561039
    title: Rab11 endosomes contribute to mitotic spindle organization and 
      orientation.
    findings: []
  - id: PMID:24769233
    title: 'Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive
      dataset.'
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:26214738
    title: Regulation of mitochondrial morphology and function by stearoylation 
      of TFR1.
    findings: []
  - id: PMID:26590417
    title: Establishment and Dysfunction of the Blood-Brain Barrier.
    findings: []
  - id: PMID:26642240
    title: A missense mutation in TFRC, encoding transferrin receptor 1, causes 
      combined immunodeficiency.
    findings: []
  - id: PMID:29302006
    title: Transferrin receptor 1 is a reticulocyte-specific receptor for 
      Plasmodium vivax.
    findings: []
  - id: PMID:29388418
    title: Transferrin Receptors TfR1 and TfR2 Bind Transferrin through 
      Differing Mechanisms.
    findings: []
  - id: PMID:29950717
    title: Cryo-EM structure of an essential Plasmodium vivax invasion complex.
    findings: []
  - id: PMID:30280653
    title: 'Blood-Brain Barrier: From Physiology to Disease and Back.'
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:38625739
    title: The secreted micropeptide C4orf48 enhances renal fibrosis via an 
      RNA-binding mechanism.
    findings: []
  - id: PMID:6090955
    title: Primary structure of human transferrin receptor deduced from the mRNA
      sequence.
    findings: []
  - id: PMID:7556058
    title: A novel iron uptake mechanism mediated by GPI-anchored human p97.
    findings: []
  - id: PMID:8394993
    title: Differential effects of antimycin A on endocytosis and exocytosis of 
      transferrin also are observed for internalization and externalization of 
      beta-adrenergic receptors.
    findings: []
  - id: PMID:9465039
    title: The hemochromatosis gene product complexes with the transferrin 
      receptor and lowers its affinity for ligand binding.
    findings: []
  - id: PMID:9546397
    title: Crystal structure of the hemochromatosis protein HFE and 
      characterization of its interaction with transferrin receptor.
    findings: []
  - id: PMID:9990067
    title: Association of HFE protein with transferrin receptor in crypt 
      enterocytes of human duodenum.
    findings: []
  - id: Reactome:R-HSA-5691154
    title: HFE binds TFRC dimer
    findings: []
  - id: Reactome:R-HSA-8866277
    title: AP-2 directly binds some endocytic cargo
    findings: []
  - id: Reactome:R-HSA-8867754
    title: F- and N- BAR domain proteins bind the clathrin-coated pit
    findings: []
  - id: Reactome:R-HSA-8867756
    title: CLASP proteins and cargo are recruited to the nascent clathrin-coated
      pit
    findings: []
  - id: Reactome:R-HSA-8868071
    title: Clathrin recruits PIK3C2A
    findings: []
  - id: Reactome:R-HSA-8868072
    title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
    findings: []
  - id: Reactome:R-HSA-8868230
    title: SNX9 recruits components of the actin polymerizing machinery
    findings: []
  - id: Reactome:R-HSA-8868236
    title: BAR domain proteins recruit dynamin
    findings: []
  - id: Reactome:R-HSA-8868648
    title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
    findings: []
  - id: Reactome:R-HSA-8868651
    title: Endophilins recruit synaptojanins to the clathrin-coated pit
    findings: []
  - id: Reactome:R-HSA-8868658
    title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
    findings: []
  - id: Reactome:R-HSA-8868659
    title: Clathrin recruits auxilins to the clathrin-coated vesicle
    findings: []
  - id: Reactome:R-HSA-8868660
    title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
    findings: []
  - id: Reactome:R-HSA-8868661
    title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
    findings: []
  - id: Reactome:R-HSA-8869438
    title: Dissociation of clathrin-associated proteins
    findings: []
  - id: Reactome:R-HSA-8871193
    title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
    findings: []
  - id: Reactome:R-HSA-8871194
    title: RAB5 and GAPVD1 bind AP-2
    findings: []
  - id: Reactome:R-HSA-917807
    title: holoTF:TFRC dimer translocates from plasma membrane to endosome 
      membrane
    findings: []
  - id: Reactome:R-HSA-917814
    title: apoTF:TFRC dimer translocates from endosome membrane to plasma 
      membrane
    findings: []
  - id: Reactome:R-HSA-917835
    title: Fe3+ dissociates from holoTF:TFRC dimer
    findings: []
  - id: Reactome:R-HSA-917839
    title: apo-Transferrin dissociates from the receptor complex
    findings: []
  - id: Reactome:R-HSA-917987
    title: TFRC dimer binds 2xholoTF
    findings: []
  - id: file:human/TFRC/TFRC-deep-research-perplexity.md
    title: Deep research on TFRC function
    findings: []
tags:
  - ferroptosis

TFRC

Gene Description