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Cited by 141Iron Metabolism and DisordersRNA Research and SplicingCellular transport and secretion

The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.

Alternative Splicing Regulates the Subcellular Localization of Divalent Metal Transporter 1 Isoforms

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Tabuchi, Mitsuaki, Tanaka, Naotaka, Nishida-Kitayama, Junko, Ohno, Hiroshi, Kishi, Fumio·2002·Molecular Biology of the Cell
DOI 10.1091/mbc.e02-03-0165PMC PMC138640
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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.

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  1. Andrews N.C., 1998, Blood, 92, 1845, 10.1182/blood.V92.6.1845 · DOI
  2. Canonne-Hergaux F., 2000, Blood, 96, 3964
  3. Ponka P., 1998, Semin. Hematol., 35, 35
  4. Oates P.S., 1996, Am. J. Physiol., 270, G826

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Metadata

Authors
Tabuchi, M., Tanaka, N., Nishida-Kitayama, J., Ohno, H., & Kishi, F.
Affiliations
  • Yamaguchi University (JP)
  • Kanazawa University (JP)
  • Center for Gene Research, Yamaguchi University, 1–1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan;
  • Kagoshima University (JP)
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2002-12
Volume
13
Issue
12
Pages
4371-4387
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e02-03-0165
PMC
PMC138640
OpenAlex
W2099892653
Cited by
141
References
52
Citations by year
2026: 2 · 2025: 8 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 9 · 2015: 8 · 2014: 3 · 2013: 3 · 2012: 7
FWCI
3.68
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Japan Science Society
  • Directorate for Biological Sciences
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
DMT1, alternative splicing, protein isoforms, subcellular localization, iron absorption, endosomal trafficking, early endosomes, late endosomes, lysosomes, apical membrane, cell polarity, N-glycosylation, cytoplasmic tail, iron-responsive element, cell type-specific gene expression
MeSH terms
Solute Carrier Family 11, Member 2, Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cytoplasm, Detergents, Dogs, Electrophoresis, Polyacrylamide Gel, Epithelial Cells, Exons, Genetic Complementation Test, Glycosylation, Humans, Iron, Microscopy, Fluorescence, Models, Biological, Molecular Sequence Data, Phenotype, Plasmids, Schizosaccharomyces, Subcellular Fractions, Transfection, Tumor Cells, Cultured, Immunoblotting, Blotting, Western, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Alternative Splicing, Protein Structure, Tertiary, Biotinylation, Protein Isoforms, Membrane Microdomains, Cation Transport Proteins, Iron-Binding Proteins, Mice, Rats

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