• T9
• transferrin receptor

MAJOR LINKS FOR CD71  

• NCBI LocusLink Record: 7037
• Mendelian Inheritance in Man (OMIM): 190010
• SwissProt annotated protein record: P02786

• Binds transferrin and hence mediates uptake of iron

CELLULAR FUNCTION OF CD71  

• Iron uptake. Ferrotransferrin binds to CD71 at neutral pH and is internalized to an acidic endosomal compartment where the pH is about 5. Iron is released and transported into the cytoplasm by an as yet poorly understood process
• Iron-free apotransferrin remains bound to CD71 at pH 5, and is returned to the cell surface, where the pH rises to about 7.4. At neutral pH, apotransferrin loses its affinity for the receptor, and is released into the circulation, allowing a new cycle to begin

DISEASE RELEVANCE OF CD71 AND FUNCTION OF CD71 IN INTACT ANIMAL  

• Uptake of iron. Has been used as target for antibodies to inhibit proliferation, and also to target cytotoxic molecules to proliferating cells
• Transferrin receptor has also been used to transfect DNA into cells ("transferrinfection")

• Families in which CD71 is a member
  • CD71-->transferrin receptor

MOLECULAR STRUCTURE OF CD71  

• Disulfide-bonded homodimeric type II transmembrane molecule (about 760 amino acids)
• About 671 amino acid extracellular C-terminal domain (binds transferrin)
• 28 amino acid transmembrane domain
• 61 amino acid N-terminal cytoplasmic tail (mediates rapid endocytosis and recycling)

MOLECULAR MASS OF CD71  

POST-TRANSCRIPTIONAL MODIFICATION OF CD71  

• mRNA has unusually long 3' untranslated region (about 3 kb) which contains stem and loop structures known as Iron-Regulating Elements (IREs), which bind to Iron-Regulatory Proteins (IRP-1 and IRP-2), which stabilize the mRNA
• In iron-replete cells, IRP-1 and IRP-2 lose their affinity for CD71 mRNA and/or are degraded, and the CD71 mRNA is therefore destabilized and subject to degradation by ribonucleases. This has the effect of reducing transferrin receptor expression and lowering the uptake of iron to prevent excessive iron uptake, which could be toxic to the cell
• IRP-1 is identical to mitochondrial aconitase
• IRP-2 is homologous to aconitase, but has not yet been shown to have aconitase activity

POST-TRANSLATIONAL MODIFICATION OF CD71  

• Three N-linked glycans
• One O-linked glycan
• Cysteine close to cytoplasmic face of transmembrane region is acylated via thioester bond to palmitic acid. The functional significance is unknown
• Cytoplasmic tail phosphorylated by protein kinase C on serine/threonine, but phosphorylation does not seem to be essential for rapid endocytosis

• Transactivated by Ets-1 and probably Sp1
• MafB, an AP-1 like protein, interacts with Ets-1 and downregulates the transferrin receptor gene

SUBSTRATES FOR CD71   - No information

ENZYMES WHICH MODIFY CD71   - No information

LIGANDS FOR CD71 AND MOLECULES ASSOCIATED WITH CD71  

• Expressed, typically at high levels, on all proliferating cells. Cellular distribution reflects need for iron
• Reticulocytes, erythroid precursors (unlike other cell types, the need for iron and proliferation are not related in erythroid cells, because the need for iron is related to haem synthesis and differentiation rather than proliferation)
• Capillary endothelium in brain

• The N-terminal intracellular domain mediates rapid endocytosis and recycling. The critical feature for endocytosis seems to be located in a highly conserved tetrapeptide YTRF, with a tyrosine located in a tight turn (see Trowbridge et al., 1993)
• The proteins interacting with the cytoplasmic tail that mediate rapid endocytosis are still not completely identified
• Transferrin receptors of human, mouse, rat, Chinese hamster, and chicken all possess a highly conserved RGD sequence flanked by hydrophobic residues (see Ruoslahti and Pierschbacher 1987). The significance of this fortransferrin binding or other function is currently unknown, but it could suggest an evolutionary link with cell adhesion molecules
• Insects have been shown to have a transferrin-related molecule (Jamroz et al., 1993), which suggests that they might have transferrin receptors
• A region of the transferrin receptor from Phe 237 to Ile 290 is 44% identical to a region of streptococcal C5a peptidase (Barclay et al., 1993)
• The human type II ecto-enzyme N-acetylated alpha-linked acid dipeptidase (also known as prostate-specific membrane antigen, although it is not prostate-specific) also shows significant homology to the transferrin receptor (Israeli et al. 1993, Pytowski et al. 1996)

SELECTION OF OTHER CD71-SPECIFIC REFERENCE MAB  

REVIEWS

1. Hentze MW,Kuhn LC Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci U S A 1996 93:8175 PubMed

2. Trowbridge IS,Collawn JF,Hopkins CR Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Biol 1993 9:129 PubMed

PRIMARY CITATIONS

3. Barclay, A.N., Birkeland, M.L, Brown, M.H., Beyers, B.D., Davis, S.J., Somoza, C., and Williams, A.F. (1993) In The Leucocyte Antigen Facts Book (ed A.N. Barclay et al.), pp 258-259. Academic Press, London (1993).

4. Goding JW,Burns GF Monoclonal antibody OKT-9 recognizes the receptor for transferrin on human acute lymphocytic leukemia cells. J Immunol 1981 127:1256 PubMed

5. Goding JW,Harris AW Subunit structure of cell surface proteins: disulfide bonding in antigen receptors, Ly-2/3 antigens, and transferrin receptors of murine T and B lymphocytes. Proc Natl Acad Sci U S A 1981 78:4530 PubMed

6. Israeli RS,Powell CT,Fair WR,Heston WD Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res 1993 53:227 PubMed

7. Jamroz RC,Gasdaska JR,Bradfield JY,Law JH Transferrin in a cockroach: molecular cloning, characterization, and suppression by juvenile hormone. Proc Natl Acad Sci U S A 1993 90:1320 PubMed

8. Kuhn LC,McClelland A,Ruddle FH Gene transfer, expression, and molecular cloning of the human transferrin receptor gene. Cell 1984 37:95 PubMed

9. Pytowski B,Judge TW,McGraw TE An internalization motif is created in the cytoplasmic domain of the transferrin receptor by substitution of a tyrosine at the first position of a predicted tight turn. J Biol Chem 1995 270:9067 PubMed

10. Ruoslahti E,Pierschbacher MD New perspectives in cell adhesion: RGD and integrins. Science 1987 238:491 PubMed

11. Schneider C,Owen MJ,Banville D,Williams JG Primary structure of human transferrin receptor deduced from the mRNA sequence. Nature 1984 311:675 PubMed

12. Schneider C,Sutherland R,Newman R,Greaves M Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9. J Biol Chem 1982 257:8516 PubMed

13. Sutherland R,Delia D,Schneider C,Newman R,Kemshead J,Greaves M Ubiquitous cell-surface glycoprotein on tumor cells is proliferation- associated receptor for transferrin. Proc Natl Acad Sci U S A 1981 78:4515 PubMed

14. Trowbridge IS,Omary MB Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc Natl Acad Sci U S A 1981 78:3039 PubMed

15. van Driel IR,Stearne PA,Grego B,Simpson RJ,Goding JW The receptor for transferrin on murine myeloma cells: one-step purification based on its physiology, and partial amino acid sequence. J Immunol 1984 133:3220 PubMed

WWW RESOURCES

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Modified 10/14/99   mpr@mail.nih.gov