Transferrin Receptor 2 as a Signaling Receptor

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Transferrin receptor 2 (TfR2) is a transferrin-binding protein predominantly found in liver and intestine. Its abundance is generally opposite that of TfR1, a more ubiquitously present protein that is responsible for the uptake of iron into cells. Mutations in the gene encoding TfR2 (or knockout in mice) produce hemochromatosis and iron loading in the liver, suggesting a role for TfR2 in organismal iron homeostasis. Calzolari et al . used various methods to show that TfR2 was present in lipid raft domains in cultured HepG2 or K562 cells and that TfR2 coimmunoprecipitated with caveolin-1 and colocalized with the tetraspanin CD81. Although the protein was most abundant in the plasma membrane, where lipid raft association was increased in the presence of holotransferrin, the majority of intracellular TfR2 was in a compartment distinct from that in which TfR1 was found. Using sucrose gradient centrifugation, the authors separated exosomes from plasma membrane from lipid raft domains and found that TfR1 and TfR2 were present in exosome preparations, along with CD81. Surprisingly, TfR1 and TfR2 appeared to be present on separate populations of exosomes, in that isolated TfR2-positive exosomes did not cross-react with antibodies that recognized TfR1. When K562 cells were serum starved and then exposed to either human transferrin (binds to both TfR1 and TfR2) or bovine transferrin (binds only to TfR2) or to an antibody that cross-links TfR2, the cells exhibited a transient increase in extracellular signal-regulated kinase (ERK) phosphorylation, suggesting activation of the mitogen-activated protein kinase (MAPK) pathway. Cholesterol depletion inhibited the phosphorylation of ERK stimulated by the antibody against TfR2, suggesting that raft association was important for TfR2 to activate the MAPK pathway. This signaling connection supports the hypothesis that TfR2 serves as a sensor of hepatic iron status to regulate the activity of hepcidin, which is a hormone released by the liver that inhibits intestinal iron absorption and iron release by macrophages. A. Calzolari, C. Raggi, S. Deaglio, N. M. Sposi, M. Stafsnes, K. Fecchi, I. Parolini, F. Malavasi, C. Peschle, M. Sargiacomo, U. Testa, TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J. Cell Sci. 119 , 4486-4498 (2006). [Abstract] [Full Text]