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. Useful in studies of dividing haematopoietic and tumour cell populations, and metabolic activity. A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C terminal binding site. The antigen is present on most dividing cells, including normally cycling in vivo hematopoietic progenitor cells, mitogenically stimulated cells in vitro, some primary tumor cells and most proliferating cells in vitro.