TISIDB

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cell membrane Single-pass type II membrane protein Melanosome Note=Identified by mass spectrometry in melanosome fractions from stage I to stage IV. ; SUBCELLULAR LOCATION: Transferrin receptor protein 1, serum form: Secreted
Domain	PF02225 PA domain PF04389 Peptidase family M28 PF04253 Transferrin receptor-like dimerisation domain
Function	Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site. Positively regulates T and B cell proliferation through iron uptake (PubMed:26642240). ; FUNCTION: (Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus.

> Gene Ontology [ TOP ]
Biological Process	GO:0000018 regulation of DNA recombination GO:0000041 transition metal ion transport GO:0001894 tissue homeostasis GO:0002200 somatic diversification of immune receptors GO:0002204 somatic recombination of immunoglobulin genes involved in immune response GO:0002208 somatic diversification of immunoglobulins involved in immune response GO:0002250 adaptive immune response GO:0002263 cell activation involved in immune response GO:0002285 lymphocyte activation involved in immune response GO:0002312 B cell activation involved in immune response GO:0002366 leukocyte activation involved in immune response GO:0002377 immunoglobulin production GO:0002381 immunoglobulin production involved in immunoglobulin mediated immune response GO:0002440 production of molecular mediator of immune response GO:0002443 leukocyte mediated immunity GO:0002449 lymphocyte mediated immunity GO:0002460 adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002521 leukocyte differentiation GO:0002562 somatic diversification of immune receptors via germline recombination within a single locus GO:0002573 myeloid leukocyte differentiation GO:0002637 regulation of immunoglobulin production GO:0002639 positive regulation of immunoglobulin production GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002697 regulation of immune effector process GO:0002699 positive regulation of immune effector process GO:0002700 regulation of production of molecular mediator of immune response GO:0002702 positive regulation of production of molecular mediator of immune response GO:0002703 regulation of leukocyte mediated immunity GO:0002705 positive regulation of leukocyte mediated immunity GO:0002706 regulation of lymphocyte mediated immunity GO:0002708 positive regulation of lymphocyte mediated immunity GO:0002712 regulation of B cell mediated immunity GO:0002714 positive regulation of B cell mediated immunity GO:0002819 regulation of adaptive immune response GO:0002821 positive regulation of adaptive immune response GO:0002822 regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002824 positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002889 regulation of immunoglobulin mediated immune response GO:0002891 positive regulation of immunoglobulin mediated immune response GO:0006310 DNA recombination GO:0006826 iron ion transport GO:0006875 cellular metal ion homeostasis GO:0006879 cellular iron ion homeostasis GO:0006898 receptor-mediated endocytosis GO:0007159 leukocyte cell-cell adhesion GO:0015682 ferric iron transport GO:0016064 immunoglobulin mediated immune response GO:0016444 somatic cell DNA recombination GO:0016445 somatic diversification of immunoglobulins GO:0016447 somatic recombination of immunoglobulin gene segments GO:0019058 viral life cycle GO:0019724 B cell mediated immunity GO:0022407 regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0030099 myeloid cell differentiation GO:0030260 entry into host cell GO:0030316 osteoclast differentiation GO:0030888 regulation of B cell proliferation GO:0030890 positive regulation of B cell proliferation GO:0031623 receptor internalization GO:0032844 regulation of homeostatic process GO:0032846 positive regulation of homeostatic process GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032946 positive regulation of mononuclear cell proliferation GO:0033572 transferrin transport GO:0034103 regulation of tissue remodeling GO:0034105 positive regulation of tissue remodeling GO:0035690 cellular response to drug GO:0042098 T cell proliferation GO:0042100 B cell proliferation GO:0042102 positive regulation of T cell proliferation GO:0042110 T cell activation GO:0042113 B cell activation GO:0042129 regulation of T cell proliferation GO:0042493 response to drug GO:0043112 receptor metabolic process GO:0044409 entry into host GO:0045124 regulation of bone resorption GO:0045190 isotype switching GO:0045191 regulation of isotype switching GO:0045453 bone resorption GO:0045780 positive regulation of bone resorption GO:0045785 positive regulation of cell adhesion GO:0045830 positive regulation of isotype switching GO:0045911 positive regulation of DNA recombination GO:0046651 lymphocyte proliferation GO:0046718 viral entry into host cell GO:0046849 bone remodeling GO:0046850 regulation of bone remodeling GO:0046852 positive regulation of bone remodeling GO:0046916 cellular transition metal ion homeostasis GO:0048771 tissue remodeling GO:0048871 multicellular organismal homeostasis GO:0050670 regulation of lymphocyte proliferation GO:0050671 positive regulation of lymphocyte proliferation GO:0050863 regulation of T cell activation GO:0050864 regulation of B cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050870 positive regulation of T cell activation GO:0050871 positive regulation of B cell activation GO:0051052 regulation of DNA metabolic process GO:0051054 positive regulation of DNA metabolic process GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0051701 interaction with host GO:0051806 entry into cell of other organism involved in symbiotic interaction GO:0051828 entry into other organism involved in symbiotic interaction GO:0055072 iron ion homeostasis GO:0055076 transition metal ion homeostasis GO:0060249 anatomical structure homeostasis GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0070661 leukocyte proliferation GO:0070663 regulation of leukocyte proliferation GO:0070665 positive regulation of leukocyte proliferation GO:0071593 lymphocyte aggregation GO:0072512 trivalent inorganic cation transport GO:0097286 iron ion import GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion
Molecular Function	GO:0001618 virus receptor activity GO:0001948 glycoprotein binding GO:0003725 double-stranded RNA binding GO:0004998 transferrin receptor activity GO:0005381 iron ion transmembrane transporter activity GO:0008320 protein transmembrane transporter activity GO:0008565 protein transporter activity GO:0015091 ferric iron transmembrane transporter activity GO:0015399 primary active transmembrane transporter activity GO:0015405 P-P-bond-hydrolysis-driven transmembrane transporter activity GO:0015450 P-P-bond-hydrolysis-driven protein transmembrane transporter activity GO:0022804 active transmembrane transporter activity GO:0022884 macromolecule transmembrane transporter activity GO:0033570 transferrin transmembrane transporter activity GO:0038024 cargo receptor activity GO:0046873 metal ion transmembrane transporter activity GO:0046915 transition metal ion transmembrane transporter activity GO:0072510 trivalent inorganic cation transmembrane transporter activity
Cellular Component	GO:0005905 clathrin-coated pit GO:0009897 external side of plasma membrane GO:0016323 basolateral plasma membrane GO:0042470 melanosome GO:0043235 receptor complex GO:0048770 pigment granule GO:0055037 recycling endosome GO:0072562 blood microparticle GO:0098552 side of membrane GO:0098589 membrane region GO:0098802 plasma membrane receptor complex GO:1990712 HFE-transferrin receptor complex

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04066 HIF-1 signaling pathway hsa04144 Endocytosis hsa04145 Phagosome hsa04640 Hematopoietic cell lineage
Reactome	R-HSA-8856825: Cargo recognition for clathrin-mediated endocytosis R-HSA-421837: Clathrin derived vesicle budding R-HSA-8856828: Clathrin-mediated endocytosis R-HSA-432722: Golgi Associated Vesicle Biogenesis R-HSA-917937: Iron uptake and transport R-HSA-199991: Membrane Trafficking R-HSA-917977: Transferrin endocytosis and recycling R-HSA-382551: Transmembrane transport of small molecules R-HSA-5653656: Vesicle-mediated transport R-HSA-199992: trans-Golgi Network Vesicle Budding

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04066 HIF-1 signaling pathway
hsa04144 Endocytosis
hsa04145 Phagosome
hsa04640 Hematopoietic cell lineage

Reactome

R-HSA-8856825: Cargo recognition for clathrin-mediated endocytosis
R-HSA-421837: Clathrin derived vesicle budding
R-HSA-8856828: Clathrin-mediated endocytosis
R-HSA-432722: Golgi Associated Vesicle Biogenesis
R-HSA-917937: Iron uptake and transport
R-HSA-199991: Membrane Trafficking
R-HSA-917977: Transferrin endocytosis and recycling
R-HSA-382551: Transmembrane transport of small molecules
R-HSA-5653656: Vesicle-mediated transport
R-HSA-199992: trans-Golgi Network Vesicle Budding

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TFRC and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between TFRC and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
17898788	Adult T-Cell Leukemia/Lymphoma	Inhibit immunity	A24 binds TfR-1 (K(d) 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1(high)), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition.
20530676	Hematopoietic and Lymphoid Cell Neoplasm	Inhibit immunity	Development of human single-chain antibodies to the transferrin receptor that effectively antagonize the growth of leukemias and lymphomas. The major route of iron uptake by cells occurs through transferrin receptor (TfR)-mediated endocytosis of diferric-charged plasma transferrin (holo-Tf). In support of this hypothesis, the anti-TfR scFvs identified were antagonists of TfR binding to holo-Tf, particularly two of the most potent antibodies, 3TF12 and 3GH7, which blocked the in vitro proliferation of a number of hematopoietic cancer cell lines. Together, our findings define a new class of fully human anti-TfR antibodies suitable for immunotherapy against tumors whose proliferation relies on high levels of TfR and iron uptake, such as acute lymphoid and myeloid leukemias.

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of TFRC in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	Second most enriched score: 0.51	Sensitive to T cell-mediated killing
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of TFRC in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.21	0.629
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	1.513	0.491
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.751	0.673
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.166	0.676
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.735	0.755
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.554	0.856
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.102	0.826
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.052	0.98
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.259	0.904
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	-0.494	0.72
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.452	0.817
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.305	0.0123

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TFRC in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	11.1	-11.1	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TFRC. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TFRC. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TFRC. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TFRC. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TFRC expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TFRC and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TFRC
Name	transferrin receptor
Aliases	CD71; TFR1; transferrin receptor (p90, CD71); TFR; TRFR; CD antigen CD71; Transferrin receptor protein 1
Chromosomal Location	3q29
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TFRC collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting TFRC.

ID	Name	Drug Type	Targets	#Targets
DB01592	Iron	Small Molecule	AHSP, CP, EGLN1, FEN1, FTH1, FXN, HBA1, HDAC8, NEIL1, NEIL2, POLB, ......	13

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