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Vol. 18, Issue 3, 743-754, March 2007

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

Martha B. Johnson^*, Juxing Chen, Nicholas Murchison, Frank A. Green, and Caroline A. Enns

Departments of *Biochemistry and Molecular Biology and Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239

Submitted September 8, 2006; Revised November 17, 2006; Accepted December 3, 2006
Monitoring Editor: Jean Gruenberg

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 (Fe₂Tf). TfR2 also binds Fe₂Tf, 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 Fe₂Tf 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 Fe₂Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe₂Tf 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 Fe₂Tf, increases the rate of receptor turnover and prevents stabilization by Fe₂Tf, indicating a direct role of Fe₂Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif.

Address correspondence to: Caroline A. Enns (ennsca{at}ohsu.edu)

Abbreviations used: Ab, antibody; AP, adaptor protein; EEA, early endosomal antigen; FBS, fetal bovine serum; Fe₂Tf, diferric transferrin; HBSS, Hanks' balanced salt solution; LAMP, lysosome-associated membrane protein; MEM, minimal essential medium; PBS, phosphate-buffered saline; Tf, transferrin; TfR, transferrin receptor; Trfr2, murine transferrin receptor 2; TGN, trans-Golgi network; WT, wild-type; YXXØ, tyrosine (Y)-based endocytic motif where X represents any amino acid and Ø represents a bulky hydrophobic residue.

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