In vertebrates all iron is taken up via the carrier protein transferrin. The carrier first binds its receptor and the receptor-ligand complex is then internalized via coated pits. Schneider et al reported the isolation of cDNA clones for the human transferrin receptor. The transferrin receptor is a transmembrane glycoprotein (apparent molecular weight (MW) 180,000) composed of two disulphide-bonded sub-units (each of apparent MW 90,000) It contains three N-linked glycan units and is post-translationally modified with both phosphate and fatty acyl groups.
The receptor does not contain an N-terminal signal peptide but there is a membrane-spanning segment 62 amino acids from the N-terminus. It therefore has a somewhat unusual configuration with a small N-terminal cytoplasmic domain and a C-terminal extracellular domain of 672 amino acids.
NCBI Summary:
This gene encodes a cell surface receptor necessary for cellular iron uptake by the process of receptor-mediated endocytosis. This receptor is required for erythropoiesis and neurologic development. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]
General function
Receptor, Cell death/survival, DNA Replication
Comment
Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor by receptor-mediated endocytosis. Iron is dissociated from transferrin in a nonlysosomal acidic compartment of the cell. Provision of intracellular iron for synthesis of ribonucleotide reductase, an enzyme that catalyzes the first step leading to DNA synthesis, is required for cell division. After dissociation of iron, transferrin and its receptor return undegraded to the extracellular environment and the cell membrane, respectively.
Transferrin receptor-mediated reactive oxygen species promotes ferroptosis of KGN cells via regulating NADPH oxidase 1/PTEN induced kinase 1/acyl-CoA synthetase long chain family member 4 signaling. Zhang L et al. (2021) Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Abnormal ovarian folliculogenesis is the main factor responsible for PCOS. Iron metabolism plays a vital role in endocrine disorder. This study aimed to investigate the potentials of iron metabolism in PCOS and the underlying molecular mechanisms. Mice were injected with dehydroepiandrosterone (DHEA) to establish the PCOS model in-vivo. H & E staining was performed for histological analysis; qRT-PCR and western blot were employed to determine the mRNA and protein expressions. Immunofluorescence was used for mitochondrial staining. Cellular functions were detected using CCK-8 and PI staining assays. Ferric ammonium citrate (FAC) activates the transferrin receptor (TFRC), increases the iron content, and suppresses the cell viability of the human granulosa-like tumor cell line (KGN). However, TFRC knockdown suppressed ferroptosis of KGN cells. Iron uptake mediated the activation of NADPH oxidase 1 (NOX1) signaling, which induced the release of reactive oxygen species (ROS) and mitochondrial damage. Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation. Additionally, FAC increased iron uptake and suppressed the folliculogenesis in-vivo. In conclusion, TFRC increased the iron content, mediated the release of ROS, activated mitophagy, and induced lipid peroxidation, which further promoted the ferroptosis of KGN cells. Therefore, the inhibitory effects of TFRC/NOX1/PINK1/ACSL4 signaling on folliculogenesis can be a potential target for PCOS.Figure: see text].//////////////////Serum-free media for cultured granulosa cells and follicles are routinely, supplemented with insulin, transferrin , and selenium (for example see [Barano et al., 1985;Eppig et al. ,1998). Yu et al. (1991) reported an inhibitory effect of transferrin on differentiation of rat granulosa cells in vitro. They indicated that 1) transferrin may be an important negative modulator of the stimulatory actions of FSH or IGF-I and other factors acting on granulosa cells; 2) the inhibitory effects of transferrin require the presence of FSH or other factors such as IGF-I or insulin, which facilitate granulosa cell differentiation; and 3) different mechanisms are involved in the modulating effects of transferrin on inhibin and progesterone production. In cultured rat granulosa cells, Li et al reported that coincubation with increasing doses of transferrin produced a dose-dependent inhibition of FSH-stimulated aromatase activity. Kawano et al. (1995) reported that progesterone production by porcine granulosa cells was suppressed by transferrin in the presence of FSH.
Immunofluorescence microscopy using specific polyclonal antisera against transferrin receptor suggested strong staining in liver and ovary (Fuernkranz et al., 1991).Based on immunostaining using monoclonal antisera, oocyte of human follicles was found to be intensely positive for transferrin receptors, but this positivity decreases in large follicles. Positive staining was also found in granulosa cells. However, not all of these cells were equally immunoreactive. An intense positivity was present in the developing
thecal cells of early antral follicles as well as in thecal cells of follicles of medium and large size and in some cells of follicles in initial atresia (Balboni et al., 1987).
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum