CD71 is the iron transferrin receptor 1 (TFRC), the major cell surface iron uptake protein. Iron uptake is mediated by the internalization of the transferrin (Tf)-iron complex through a clathrin-dependent pathway and receptor-mediated constitutive endocytosis to maintain intracellular iron homeostasis. CD71 is abundantly expressed in many tumor cells and is a potential tumor marker.

CD71 composition and distribution

CD71 is mainly expressed in cells that require a lot of iron, including cells in the hematopoietic system, cells in the immune system, and some tumor cells. These cells need CD71 to help them absorb and utilize iron to maintain their normal function and growth.

(Data source: uniprot)

CD71 structure:

CD71 is a homodimeric type II transmembrane protein composed of a small cytoplasmic domain, a single transmembrane region, and a complex extracellular domain. Each monomer of the extracellular domain is subdivided into a protease-like domain that contacts the cell membrane, a helical domain containing the dimer contact region, and an apical domain. The extracellular domain displays ligand-binding sites for multiple proteins: its basal portion (formed by the protease-like and helical domains) binds to Tf14, while the dimer interface region forms a complex with hereditary hemochromatosis factor (HFE) 17. Studies have shown that the upper portion of the apical domain interacts with the invasion protein PvRBP2b 12 of arenaviruses and Plasmodium vivax.

(Data source: Montemiglio LC, et al. Nat Commun. 2019)

Human ferritin (H-Ft) binds to CD71 in a viral-like manner, binding through four specific contact regions on CD71 that cover a total area of approximately 1900 Å2. The interaction between CD71 and H-Ft involves multiple specific residues, such as the βII-2 strand of CD71 and the A helix of H-Ft. The binding regions between CD71 and H-Ft exhibit differences between shared and exclusive contacts, and mutations in these regions on CD71 may result in increased or decreased interactions with pathogen-binding proteins. The interaction between CD71 and ferritin has implications for various physiological and pathological processes, including iron uptake, pathogen invasion, and potential therapeutic applications in nanomedicine and cancer treatment.

(Data source: Montemiglio LC, et al. Nat Commun. 2019)

CD71 function

TFRC preferentially binds to distinct Tfs, forming ligand-receptor complexes on the cell surface and constitutively internalizing the ligand-receptor complexes through clathrin-mediated endocytosis. Within endosomes, proton influx mediated by the endosomal membrane proton pump causes a decrease in pH to 5.5 (endosomal acidification), triggering conformational changes in Tf and TfR1, leading to the subsequent release of iron from Tf. Iron is then converted from Fe ³⁺ to Fe ²⁺ by the iron reductase STEAP3 and pumped out of the endosome by divalent metal transporter 1 (DMT1). The Tf/TfR1 complex is then recycled back to the cell surface, where the neutral pH of the extracellular environment favors its dissociation. In the cytoplasm, iron can be stored in ferritin nanocages due to the presence of the chaperone proteins PCBP1/2 and released upon demand by NCOA4. Excess iron is exported to the extracellular space via FPN1.

(Data source: Silvestri L, Int J Mol Sci. 2023)

Relationship between CD71 and disease

CD71 is generally overexpressed in tumor cells, with expression levels generally higher than in normal cells. TfR1 has been identified as a universal cancer marker. Increased TfR1 expression is associated with advanced stages or poor prognosis in a variety of cancers, including esophageal squamous cell carcinoma, breast cancer, ovarian cancer, lung cancer, cervical cancer, bladder cancer, pancreatic cancer, and rectal cancer.

Overexpression of TFRC is closely associated with the development and progression of colorectal cancer, while loss of TFRC leads to decreased cellular iron levels, reduced POLD1 expression, increased apoptosis, and suppressed tumor growth. TFRC-mediated iron import is crucial for maintaining nucleotide biosynthesis, DNA damage repair, and cell survival in colorectal cancer, providing a potential therapeutic strategy for the treatment of colon cancer.

(Data source Kim H, et al. Adv Sci. 2023)

TFRC is highly expressed in pancreatic cancer tissues and plays a role in the development and progression of pancreatic cancer primarily through signaling pathways, including cell adhesion molecule binding, chromosome condensation, chromosome segregation, and cell cycle checkpoints. Finally, TFRC is associated with immune phenotype and immune cell infiltration, which may impact immunotherapy. Combining TFRC-related CAR-T cells with immune checkpoint inhibition for pancreatic cancer is a potential therapeutic strategy. By targeting TFRC and inducing the patient's own immune cells to attack the tumor, it may offer new treatment options for pancreatic cancer patients.

(Data source: Haichuan Su, at al. Front Mol Biosci. 2022)

TFRC plays a crucial role in thrombosis. In injured vascular cells, TFRC participates in the ferroptosis process induced by oxidative stress and iron accumulation, which in turn promotes thrombosis. TFRC deficiency can alleviate iron overload and oxidative stress, preventing ferroptosis in injured veins and thus reducing thrombosis. TFRC interacts with the THBS1 protein, further regulating the thrombotic process by influencing THBS1 expression and the occurrence of ferroptosis. Controlling TFRC provides a new therapeutic approach for the prevention and treatment of thrombosis.

(Data source: Ma H, Huang Y, Tian W. Redox Biol. 2024)

TFR1 plays a crucial role in the development and progression of cancer and thrombosis, and is also implicated in other diseases, including neurodegenerative disorders and thalassemia. CD71 has numerous potential applications in the treatment of these diseases, including as a target for cancer therapy, a targeting molecule for drug delivery, and a potential diagnostic marker.