Transferrin Receptor 2-α Supports Cell Growth Both in Iron-chelated Cultured Cells and in Vivo

Kawabata, Hiroshi; Germain, Rasha; Vuong, Peter T.; Nakamaki, Tsuyoshi; Said, Jonathan; Koeffler, H. Phillip

doi:10.1074/jbc.m908846199

Cited by 225 publications

(185 citation statements)

References 30 publications

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“…TfR2 is expressed almost exclusively in the liver, whereas TfR1, the classic receptor generally called TfR and expressed widely, is present in modest amounts in the liver. 8 Importantly, these related receptors appear to be regulated differently, stimulate distinct downstream effectors, and are internalized by distinct mechanisms. TfR1 is internalized by hepatocytes via a clathrin-dependent mechanism, whereas TFR2 localizes to lipid rafts and interacts with caveolin-1.…”

Section: Hepatic Endocytosis: There Is Still a Lot To Learnmentioning

confidence: 99%

A stimulus needed for the study of membrane traffic in hepatocytes

2009

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A major function carried out by the liver is maintenance of the blood chemistry by the continuous secretion of many different serum proteins into the blood sinusoid, transport of solutes and xenobiotics from blood to bile, and filtration of the blood through active internalization of many different receptor-ligand complexes as well as unwanted viral and bacterial pathogens. These primary hepatic secretory and endocytic functions depend on an elaborate cytoskeletal-based vesicle trafficking system that can be modified to meet the specific tasks of moving cargo outward versus inward. Despite the seminal importance of these cell biological processes to the central function of the hepatocyte and general liver physiology, their molecular mechanisms remain poorly defined and remarkably understudied by the hepatology community. Here we provide a short overview of a few important cell biological processes that are performed by hepatocytes and require our attention to better understand liver physiology and disease.

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Section: Hepatic Endocytosis: There Is Still a Lot To Learnmentioning

confidence: 99%

A stimulus needed for the study of membrane traffic in hepatocytes

2009

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“…TfR2 differs from TfR1 in that it does not contain any iron-responsive elements in its mRNA, and its mRNA does not appear to be regulated by iron (10,19). Several studies have suggested that TfR2 is capable of binding transferrin, although with a reduced affinity (20,22,37). The role of TfR2 as a substitute for TfR1 in its absence is still elusive.…”

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confidence: 99%

Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

Wallace¹,

Summerville²,

Crampton³

et al. 2008

American Journal of Physiology-Cell Physiology

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“…TfR2 binds Tf in a pH-dependent manner, but its affinity for Fe 2 Tf (K D ϳ30 nM; Kawabata et al, 2000;West et al, 2000) is significantly lower than that of TfR1 (K D ϳ1 nM, Tsunoo and Sussman, 1983;Enns et al, 1991;Richardson and Ponka, 1997). Unlike TfR1, TfR2 expression is limited predominantly to hepatocytes (Kawabata et al, 1999;Fleming et al, 2000Fleming et al, , 2002Vogt et al, 2003;Calzolari et al, 2004;Zhang et al, 2004) and is not regulated by intracellular iron (Fleming et al, 2000;Kawabata et al, 2000Kawabata et al, , 2001. TfR2 cannot compensate for TfR1, whose knockout in mice results in embryonic lethality due to severe anemia (Levy et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway

Johnson

Chen

Murchison

et al. 2007

MBoC

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Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1), the protein that delivers iron to cells through receptor-mediated endocytosis of diferric transferrin (Fe 2 Tf). TfR2 also binds Fe 2 Tf, but it seems to function primarily in the regulation of systemic iron homeostasis. In contrast to TfR1, the trafficking of TfR2 within the cell has not been extensively characterized. Previously, we showed that Fe 2 Tf increases TfR2 stability, suggesting that trafficking of TfR2 may be regulated by interaction with its ligand. In the present study, therefore, we sought to identify the mode of TfR2 degradation, to characterize TfR2 trafficking, and to determine how Fe 2 Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe 2 Tf increases the fraction of TfR2 localizing to recycling endosomes and decreases the fraction of TfR2 localizing to late endosomes. Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to Fe 2 Tf, increases the rate of receptor turnover and prevents stabilization by Fe 2 Tf, indicating a direct role of Fe 2 Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif. INTRODUCTIONA truncation mutant of transferrin receptor 2 (TfR2), TfR2/ Y250X, causes a rare form of hereditary hemochromatosis (type 3, HFE3), an iron overload disorder characterized by excess absorption of dietary iron and consequent deposition of iron in liver and other parenchymal tissues (Camaschella et al., 1999(Camaschella et al., , 2000. The analogous mutation or knockout of Trfr2 in mice reproduces the disease phenotype (Fleming et al., 2002;Wallace et al., 2005). Thus, TfR2 is required for normal iron homeostasis.TfR2, cloned in 1999, is a homologue of transferrin receptor 1 (TfR1; Kawabata et al., 1999). The extracellular domains of the two receptors are 45% identical and 67% similar. TfR1 functions to deliver iron to cells through receptor-mediated endocytosis of its ligand transferrin (Tf), a serum protein that transports iron (Dautry-Varsat et al., 1983;Klausner et al., 1983). On the cell surface, TfR1 binds iron-saturated transferrin (Fe 2 Tf) at slightly basic pH. Fe 2 Tf-TfR1 then internalizes in clathrin-coated vesicles to early endosomes.In the acidic pH of early endosomes, iron releases from Tf, whereas Tf remains bound to TfR1. The complex then recycles, from either early or recycling endosomes, to the cell surface. At the slightly basic pH of the cell surface, TfR1 releases unsaturated Tf (apoTf) and again binds Fe 2 Tf. TfR1 expression is ubiquitous, consistent with its role in cellular iron delivery. The stability of TfR1 mRNA is negatively regulated by intracellular iron levels through iron-responsive elements (IREs) in the 3Ј untranslated region (Mattia et al., 1984;Ward et al., 1984;Rao et al., 1985;Sciot et al., 1987;Owen and Kuhn, 19...

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Transferrin Receptor 2-α Supports Cell Growth Both in Iron-chelated Cultured Cells and in Vivo

Cited by 225 publications

References 30 publications

A stimulus needed for the study of membrane traffic in hepatocytes

A stimulus needed for the study of membrane traffic in hepatocytes

Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway

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