Isoform-specific insulin receptor signaling involves different plasma membrane domains.
In pancreatic beta-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.
Uhles
Sabine
S
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Moede
Tilo
T
Leibiger
Barbara
B
Berggren
Per-Olof
PO
Leibiger
Ingo B
IB
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D022461:Caveolins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002784:Cholesterol / Q000172:deficiency; D006224:Cricetinae; D005091:Exons / Q000235:genetics; D005941:Glucokinase / Q000096:biosynthesis / Q000235:genetics; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism* / Q000648:ultrastructure; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D022461:Caveolins; D007328:Insulin; D020033:Protein Isoforms; D002784:Cholesterol; D005941:Glucokinase; D011972:Receptor, Insulin