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The transferrin receptor 1 (TFR1) controls systemic iron homeostasis, which mediates cellular iron uptake through endocytosis of iron-loaded transferrin (Tf). Iron is an indispensable element required for cell growth and proliferation, and its deficiency has been linked to tumors. Multiple proteins have been identified that participate in iron metabolism, like Tf, IRPs, Mt2.
TFR1, a key protein involved in iron metabolism, is markedly expressed in numerous types of cancer cells. Studies have demonstrated that targeting TFR1 can effectively suppress tumor growth and metastasis. Moreover, TFR1 is also implicated in other conditions such as anemia and neurodegenerative disorders, etc. Therefore, therapeutic interventions aimed at modulating cellular iron levels through TFR1 represent a promising strategy for various diseases.
Transferrin receptor protein 1 (TFR1) is a crucial type II transmembrane protein that regulates intracellular iron transport across the membrane. TFR1 comprises of two homodimeric subunits, which are linked by disulfide bonds. Each monomer consists of a short N-terminal region, a single transmembrane region, and a large extracellular C-terminal region. This C-terminal region, serving as an additional functional region, contains the same protein present in transferrin (Tf) (Figure 1) [1-3]. At present, two similar transferrin receptors, TFR1 and TFR2, have been identified. Under normal physiological conditions, TFR1 interacts with Tf to facilitate iron uptake. This bound form is the main way of iron presence in the blood [4-5].
Figure 1. TFR1 Structure [1]
TFR1, a membrane protein expressed across various cell and tissue types in the human body, plays a crucial role in facilitating iron transport and metabolism. Its extensive presence includes immune system, hematopoietic system (e.g., bone marrow stem cells, red blood cells, and leukocytes), nervous system (e.g., neurons and glial cells), reproductive system, heart, liver, and kidney. TFR1 expression levels are susceptible to various factors such as intracellular iron concentration, cellular differentiation status, hormonal regulation, and inflammatory status [6-8].
TFR1's crucial physiological function is to bind with transferrin (Tf), thus facilitating the cellular uptake of iron by endocytosis. This Tf-TFR1 system is a vital pathway for the body to acquire iron ions. The process involves the binding of Tf and iron (Fe3+ or Fe2+) and a subsequent structural change that results in encapsulation of iron ions within the protein, forming Tf-Fe2+. At physiological pH, TFR1 binds to Tf-Fe2+, and the Tf-TFR1 complex undergoes clathrin-mediated endocytosis (Figure 2) [9-11].
The intracellular Tf-TFR1 complex then proceeds to the endosome for acidification, where amino acid residues interact, causing conformational changes that lead to the release of iron ions. TFR1 is recycled to the cell surface through the Golgi complex, completing the transport of iron ions. In summary, TFR1 plays an integral role in maintaining cellular and tissue functions. Regulating TFR1 to balance intracellular iron concentration and ensure iron homeostasis is essential for optimal physiological functioning [9-11].
Figure 2. Tf-TFR1 system balances intracellular iron concentration [1]
Abnormal or reduced TFR1 expression can lead to cellular iron deficiency, whereas excess iron may catalyze the production of reactive oxygen species (ROSs) and cause biomolecule damage. Cells have developed various mechanisms to regulate TFR1 expression to ensure adequate iron while avoiding its toxicity. However, the exact mechanisms and roles of aberrant TFR1 expression in disease are incompletely understood.
Different factors may affect the expression and function of TFR1 in cells. At the transcriptional level, hypoxia-inducible factor (HIF), c-Myc, GATA1, Ets-1, erythropoietin Stat5, and other transcription factors can regulate TFR1 expression. At the post-transcriptional level, IRP1 and IRP2 binding to IRE in TFR1 mRNA are key determinants [12-14].
Meanwhile, CD133 (PROM1) acts as a negative regulator. EGF receptor, c-Abl, and MARCH8 also play a role at the post-translational level. A study revealed that FLCN can control TFR1 expression, a protein involved in iron metabolism. This control occurs during or after protein synthesis by helping the Tf-TFR1 complex interact with Rab11-bound endosomes, which circulate within the cell and return to the cell membrane (Figure 3) [12-16].
TFR1 plays a role in regulating various diseases. In glioma, TFR1 affects multiple mechanisms related to inflammation, DNA, and cell cycle regulation. TFR1 also controls important signaling pathways such as PD1, IL17, IL18, NF-kβ, FOXM1, FOCAL, and JAK-STAT pathways. Besides, TFR1 knockdown in neural stem cells caused epilepsy symptoms in mice, with changes in synaptic GluA2 expression and neurotransmitter release [17-22].
Figure 3. FLCN regulates the recycling and transport of Tf-TFR1 protein via Rab11A [16]
As a regulator of Fe transportation, TFR1 wields substantial influence over numerous health conditions. Specifically, TFRC plays a significant role in the development of anemia, neurodegenerative disorders, and a variety of cancers.
Numerous studies have shown that TFR1 is abnormally expressed in various malignant tumors, including thyroid cancer [23], esophageal squamous cell carcinoma [24], breast cancer [25], liver cancer [26], colon cancer [27], leukemia [28], lung cancer [29], pancreatic cancer [30], and nasopharyngeal cancer [30]. However, there are certain malignancies, such as prostate cancer and testicular cancer, where the expression of TFR1 is not well-defined.
In hepatocellular carcinoma, the expression of TFR1 is correlated with the concentration of methemoglobin and serum thrombospondin [26]. In breast cancer, inhibiting IRP2 expression reduces TFR1 expression and increases ferritin heavy chain expression, which represses the growth of breast cancer cells [25, 31].
In colon cancer, high expression of TFR1 activates the IL-6/IL-11-Stat3 signaling pathway, which promotes proliferation and apoptosis of colonic epithelial cells. This exacerbates colonic mucosa damage and accelerates the progression of colon cancer [27, 32].
Iron metabolism disturbances are known to be one of the pathophysiological mechanisms that trigger neurodegenerative diseases. Iron accumulation in the brain is associated with conditions such as Alzheimer's disease (AD), Parkinson's disease, and amyotrophic lateral sclerosis [33].
AD is one of the most common neurodegenerative diseases characterized by the accumulation of amyloid plaques and loss of certain neurons. Studies have shown that inhibiting the iron uptake proteins TFR1 and TF in the temporal cortex of Alzheimer's model mice, as well as reducing DMT1 expression, can effectively alleviate the iron overload state [34-35].
TFR1 binding to the transferrin (Tf) complex is crucial for cells to acquire iron during erythropoiesis. When there is a shortage of iron or an increase in erythropoiesis, TFR1 expression is increased in response [6, 36].
Clinical studies have confirmed that both expression levels of soluble transferrin receptor (sTFR1) and Tf are significantly higher than normal in thalassemic mice. Further studies have revealed that TFR1 is abnormally highly expressed in β-thalassemia precursor cells. Reducing TFR1 expression effectively regulates ineffective erythropoiesis, improving anemia and alleviating iron overload in affected mice [6, 36].
Studies suggest that TFR1 may also act as a viral receptor and participate in Hepatitis C Virus (HCV) cell entry by mediating HCV-host cell membrane fusion. Given that HCV is a major pathogen causing chronic hepatitis and primary liver cancer, the potential of TFR1 as an HCV antiviral target is subject to interest [37-39]. Furthermore, TFR1 has been discovered to regulate the transport of mGlu1 in neurons and is thought to participate in the mGlu1 signaling pathway, ultimately impacting motor coordination within the cerebellum [40-41].
Currently, several clinical drugs are being developed to target TFR1 (Table 1), which can be used to treat anemia, iron metabolism disorders, infections, neurodegenerative diseases, and cancers. Among these drugs, PPMX-T003, CX-2029, DYNE-251, and Trontinemab, are in clinical phase 1/2.
Treatments using TFR1 have shown promise in certain studies. For example, TFR1 can help treat Alzheimer's disease when combined with certain antibodies [42-43], and two other antibodies (JST-TFR09 and A24) targeting TFR1/TFRC have been found to inhibit cancer cell growth [44-45]. These findings suggest that TFR1 has the potential to be an effective target for treating multiple diseases. This gives hope that more effective treatments will become available in the future.
| Drug Name | Targets | Mechanism of action | Indications | Status(global) | Drug Type | Institutes |
|---|---|---|---|---|---|---|
| Human apotransferrin (Prothya Biosolutions) | TFR2 + TFR1 | TFR2 agonist, TFR1 stimulator | Congenital anoferritinemia; beta-thalassemia | Clinical Phase 2/3 | Protein-based drugs | Prothya Biosolutions Netherlands |
| PPMX-T003 | TFR1 | TFR1 antagonist | Large granular lymphocytic leukemia; true erythrocytosis | Clinical Phase 1/2 | Unknown |
Perseus Proteomics, Inc; Hiroshima University; Tokai University |
| CX-2029 | TFR1 | TFR1 antagonist | Diffuse large B-cell lymphoma; esophageal cancer; non-small cell lung cancer | Clinical Phase 1/2 | Monoclonal antibody; ADC | CytomX Therapeutics, Inc. |
| DYNE-251 | TFR1 | TFR1 antagonist, RNA interference | Duchenne muscular dystrophy | Clinical Phase 1/2 | Antisense oligonucleotides | Dyne Therapeutics, Inc. |
| Trontinemab | APP + TFR1 | APP inhibitors, TFR1 antagonists | Alzheimer's disease | Clinical Phase 1/2 | Bispecific antibodies | F. Hoffmann-La Roche Ltd. |
| INA-03 | TFR1 | TFR1 antagonist | Acute biphenotypic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia | Clinical Phase 1 | Biologics |
Inatherys Inatherys SAS; Institut Jean Paoli & Irene Calmettes |
| Delpacibart Etedesiran | TFR1 | TFR1 antagonist | / | Clinical stage unknown | Antibody nucleic acid coupled drugs | / |
| Delpacibart | TFR1 | TFR1 antagonist | / | Clinical stage unknown | Monoclonal antibodies | / |
| FORCE-M23D | TFR1 + Dystrophin | TFR1 antagonists, Dystrophin inhibitors | Benign pseudohypertrophic muscular dystrophy | Clinical Applications | Antibody nucleic acid coupled drugs | Dyne Therapeutics, Inc. |
| TXB4-BC1 | CD20+TFR1 | CD20 inhibitor, TFR1 antagonist | Lymphoma | Preclinical | Bispecific antibodies | Ossianix, Inc. |
| TXB4-BC3 | PDL1 + TFR1 | PDL1 inhibitors, TFR1 antagonists | Glioblastoma | Preclinical | Bispecific antibodies | Ossianix, Inc. |
| FORCE-FM10 | DUX4 + TFR1 | DUX4 inhibitor, TFR1 antagonist | Type 1a facioscapulohumeral muscular dystrophy | Preclinical | Antibody nucleic acid coupled drugs | Dyne Therapeutics, Inc. |
| INA-01 | TFR1 | TFR1 antagonist | Tumors | Preclinical | Monoclonal antibodies |
Inatherys Inatherys SAS |
| PGT (OncBioMune) | TFR1 | TFR1 stimulant | Kidney tumor, lung cancer, ovarian cancer | Preclinical | Biologics |
Theralink Technologies, Inc; OncBioMune, LLC. OncBioMune, Inc. |
| TXB4-BC2 | EGFRvIII + TFR1 | EGFRvIII antagonists, TFR1 antagonists | Glioblastoma | Preclinical | Bispecific antibodies | Ossianix, Inc. |
| Bicycle oligonucleotide therapeautics (Bicycle Therapeutics) | TFR1 | TFR1 antagonist | Neuromuscular diseases | Preclinical | Oligonucleotides |
Bisker Medical Ltd. Bicycle Therapeutics Plc; Ionis Pharmaceuticals, Inc. |
| Rutherrin | TFR1 | TFR1 antagonist | Glioblastoma, non-small cell lung cancer | Preclinical | Unknown | Theralase Technologies, Inc. |
| KB-121 | TFR1 | TFR1 antagonist | Burkitt's lymphoma, diffuse large B-cell lymphoma, high-grade B-cell lymphoma, set cell lymphoma, multiple myeloma | Preclinical | Monoclonal antibodies | Gemopharm OOO |
| TE-5200 | CD49d + TFR1 | CD49d antagonist, TFR1 antagonist | Multiple Sclerosis | Drug Discovery | Bispecific antibodies | Immunwork, Inc. |
| TE-5126 | CB + EDG6 + SIPR1 + SIPR2 + SIPR3 + TFR1 | CB antagonist + EDG6 modulator + SIPR1 modulator + SIPR2 modulator + SIPR3 modulator + TFR1 antagonist | Multiple Sclerosis | Drug Discovery | Monoclonal antibody; ADC | Immunwork, Inc. |
| TE-5300 | APP + TFR1 | APP inhibitors, TFR1 antagonists | Alzheimer's disease | Drug Discovery | Bispecific antibodies | Immunwork, Inc. |
| TXB4-LS1 | IDUA + TFR1 | IDUA inhibitor, TFR1 antagonist | Mucopolysaccharide storage disease type I | Drug Discovery | Fusion proteins | Ossianix, Inc. |
| Monoclonal antibody 42/6 | TFR1 | TFR1 antagonist | / | Clinical Phase 1 | Monoclonal antibodies | / |
| MAT-201 | TFR1 | TFR1 antagonist | / | Drug Discovery | Monoclonal antibodies | / |
| Lysosomal storage disease therapeutics (bioOasis) | TFR1 | TFR1 modulators, enzyme substitutes | / | Drug Discovery | Enzymes; coupled drugs | / |
| Anti-CD19 monoclonal antibody-liposomal sodium butyrate conjugate | TFR1 | TFR1 antagonist | / | / | Monoclonal antibody; ADC | / |
Table 1: Clinical drugs in development for TFR1
To fully support researchers and pharmaceutical companies in their research on TFR1 in diabetes, obesity, and cancers, CUSABIO presents TFR1 active protein to support your research on the mechanism of TFR1 or its potential clinical value (click for the full list of TFR1 products: TFR1 Proteins; TFR1 antibodies).
Recombinant Human Transferrin receptor protein 1(TFRC),partial (Active) (Code: CSB-MP3648HU)
High specificity was validated by SDS-PAGE. SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human TFRC at 2μg/mL can bind Anti-TFRC recombinant antibody (CSB-RA023441MA1HU), the EC50 is 3.305-8.220 ng/mL.
References
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