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PMID:12475959
| Citation |
Tabuchi, M, Tanaka, N, Nishida-Kitayama, J, Ohno, H and Kishi, F (2002) Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol. Biol. Cell 13:4371-87 |
|---|---|
| Abstract |
Divalent metal transporter 1 (DMT1) is responsible for dietary-iron absorption from apical plasma membrane in the duodenum and iron acquisition from the transferrin cycle endosomes in peripheral tissues. Two isoforms of the DMT1 transcript generated by alternative splicing of the 3' exons have been identified in mouse, rat, and human. These isoforms can be distinguished by the different C-terminal amino acid sequences and by the presence (DMT1A) or absence (DMT1B) of an iron response element located in the 3' untranslated region of the mRNA. However, it has been still unknown whether the structural differences between the two DMT1 isoforms is functionally important. Here, we report that each DMT1 isoform exhibits a differential cell type-specific expression patterns and distinct subcellular localizations. DMT1A is predominantly expressed by epithelial cell lines, whereas DMT1B is expressed by the blood cell lines. In HEp-2 cells, GFP-tagged DMT1A is localized in late endosomes and lysosomes, whereas GFP-tagged DMT1B is localized in early endosomes. Using site-directed mutagenesis, a Y(555)XLXX sequence in the cytoplasmic tail of DMT1B has been identified as an important signal sequence for the early endosomal-targeting of DMT1B. In polarized MDCK cells, GFP-tagged DMT1A and DMT1B are localized in the apical plasma membrane and their respective specific endosomes. Disruption of the N-glycosylation sites in each of the DMT1 isoforms affects their polarized distribution into the apical plasma membrane but not their correct endosomal localization. Our data indicate that the cell type-specific expression patterns and the distinct subcellular localizations of two DMT1 isoforms may be involved in the different iron acquisition steps from the subcellular membranes in various cell types. |
| Links |
PubMed PMC138640 Online version:10.1091/mbc.E02-03-0165 |
| Keywords |
Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Biotinylation; Blotting, Western; Cation Transport Proteins/biosynthesis; Cation Transport Proteins/chemistry; Cell Line; Cytoplasm/metabolism; Detergents/pharmacology; Dogs; Electrophoresis, Polyacrylamide Gel; Epithelial Cells/metabolism; Exons; Genetic Complementation Test; Glycosylation; Humans; Immunoblotting; Iron/metabolism; Iron-Binding Proteins/biosynthesis; Iron-Binding Proteins/chemistry; Membrane Microdomains/metabolism; Mice; Microscopy, Fluorescence; Models, Biological; Molecular Sequence Data; Mutagenesis, Site-Directed; Phenotype; Plasmids/metabolism; Protein Isoforms; Protein Structure, Tertiary; Rats; Schizosaccharomyces; Sequence Homology, Amino Acid; Subcellular Fractions; Transfection; Tumor Cells, Cultured |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0005769: early endosome |
ECO:0000314: |
C |
complete | |||||
| GO:0009986: cell surface |
ECO:0000314: |
C |
complete | |||||
| GO:0005764: lysosome |
ECO:0000314: |
C |
complete | |||||
| GO:0015082: di-, tri-valent inorganic cation transmembrane transporter activity |
ECO:0000316: |
UniProtKB:Q10177 |
F |
P49281-1 |
complete | |||
| GO:0048471: perinuclear region of cytoplasm |
ECO:0000314: |
C |
P49281-2 |
complete | ||||
|
part_of |
GO:0009986: cell surface |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005769: early endosome |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0048471: perinuclear region of cytoplasm |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
enables |
GO:0022890: inorganic cation transmembrane transporter activity |
ECO:0000316: genetic interaction evidence used in manual assertion |
UniProtKB:Q10177 |
F |
Seeded From UniProt |
complete | ||
|
part_of |
GO:0016324: apical plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005770: late endosome |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005764: lysosome |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0009986: cell surface |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005769: early endosome |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0048471: perinuclear region of cytoplasm |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
enables |
GO:0022890: inorganic cation transmembrane transporter activity |
ECO:0000316: genetic interaction evidence used in manual assertion |
UniProtKB:Q10177 |
F |
Seeded From UniProt |
complete | ||
|
part_of |
GO:0016324: apical plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005770: late endosome |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005764: lysosome |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
See also
References
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