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Isoform-specific insulin receptor signaling involves different plasma membrane domains
Sabine Uhles1, Tilo Moede, Barbara Leibiger
1The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden.
The Journal of Cell Biology
|December 24, 2003
Summary
Insulin receptor isoforms (Ex11- and Ex11+) regulate insulin and glucokinase gene transcription through distinct plasma membrane localizations, not internalization differences. This localization, dictated by exon 11, guides selective signaling pathways.
Area of Science:
- Molecular Endocrinology
- Cell Biology
- Gene Regulation
Background:
- Insulin selectively up-regulates insulin and glucokinase gene transcription in pancreatic beta-cells.
- This regulation involves two insulin receptor (IR) isoforms: A-type (IR-A, Ex11-) and B-type (IR-B, Ex11+).
- The precise molecular mechanisms enabling distinct signaling pathways activated by these IR isoforms remain elusive.
Purpose of the Study:
- To elucidate the molecular mechanism underlying selective signaling cascade activation by IR-A and IR-B.
- To determine whether receptor internalization or plasma membrane localization dictates isoform-specific promoter activation.
- To investigate the role of exon 11 in IR localization and function.
Main Methods:
- Investigated insulin promoter activation via IR-A and glucokinase promoter activation via IR-B.
- Assessed the role of receptor internalization and plasma membrane localization in isoform-specific signaling.
- Analyzed the function of the 12-amino acid string encoded by exon 11 as a sorting signal.
- Examined signaling from noncaveolae lipid rafts and their sensitivity to cholesterol depletion.
Main Results:
- Selective activation of insulin and glucokinase promoters is mediated by differential localization of IR-A and IR-B in the plasma membrane, not by internalization differences.
- The 12-amino acid sequence encoded by exon 11 functions as a critical sorting signal, determining IR localization and subsequent signaling.
- Signaling originates from noncaveolae lipid rafts with varying sensitivities to cholesterol depletion, contributing to isoform-specific promoter activation.
Conclusions:
- Plasma membrane localization, governed by the exon 11-encoded sorting signal, is the key determinant of insulin receptor isoform-specific signaling.
- This differential localization enables selective activation of insulin and glucokinase gene transcription.
- Noncaveolae lipid rafts play a crucial role in mediating these isoform-specific signaling events.