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Published 22 December 2003. doi:10.1083/jcb.200306093
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© The Rockefeller University Press, 0021-9525/2003/12/1327 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1327-1337

Article

Isoform-specific insulin receptor signaling involves different plasma membrane domains



Sabine Uhles, Tilo Moede, Barbara Leibiger, Per-Olof Berggren and 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: ingo.leibiger{at}molmed.ki.se

In pancreatic ß-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.

Key Words: lipid rafts; fluorescent protein; signal transduction; insulin; glucokinase

Abbreviations used in this paper: ßCD, ß-cyclodextrin; ßGK, ß-cell glucokinase; FRET, fluorescence resonance energy transfer; IR, insulin receptor.


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