In pancreatic β-cells, insulin selectively up-regulates the transcription of its own gene and that of the glucokinase gene by signaling through the two isoforms of the insulin receptor, i.e., A-type (Ex11−) and B-type (Ex11+), using different signaling pathways. However, the molecular mechanism(s) that allows the discrete activation of signaling cascades via the two receptor isoforms remains unclear. Here we show that activation of the insulin promoter via A-type and of the glucokinase promoter via B-type insulin receptor is not dependent on receptor isoform–specific differences in internalization but on the different localization of the receptor types in the plasma membrane. Our data demonstrate that localization and function of the two receptor types depend on the 12–amino acid string encoded by exon 11, which acts as a sorting signal rather than as a physical spacer. Moreover, our data suggest that selective activation of the insulin and glucokinase promoters occurs by signaling from noncaveolae lipid rafts that are differently sensitive toward cholesterol depletion.
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22 December 2003
Article|
December 22 2003
Isoform-specific insulin receptor signaling involves different plasma membrane domains
Sabine Uhles,
Sabine Uhles
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
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Tilo Moede,
Tilo Moede
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
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Barbara Leibiger,
Barbara Leibiger
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
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Per-Olof Berggren,
Per-Olof Berggren
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
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Ingo B. Leibiger
Ingo B. Leibiger
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
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Sabine Uhles
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
Tilo Moede
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
Barbara Leibiger
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
Per-Olof Berggren
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
Ingo B. Leibiger
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden
Address correspondence to Ingo B. Leibiger, Karolinska Institutet, Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research L3, S-171 76 Stockholm, Sweden. Tel.: 46-8-5177 5725. Fax: 46-8-5177 9450. email: [email protected]
Abbreviations used in this paper: βCD, β-cyclodextrin; βGK, β-cell glucokinase; FRET, fluorescence resonance energy transfer; IR, insulin receptor.
Received:
June 18 2003
Accepted:
November 03 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 163 (6): 1327–1337.
Article history
Received:
June 18 2003
Accepted:
November 03 2003
Citation
Sabine Uhles, Tilo Moede, Barbara Leibiger, Per-Olof Berggren, Ingo B. Leibiger; Isoform-specific insulin receptor signaling involves different plasma membrane domains . J Cell Biol 22 December 2003; 163 (6): 1327–1337. doi: https://doi.org/10.1083/jcb.200306093
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