Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors.
The specific contribution of insulin and IGF-I receptors to IRS-protein activation remains elusive. We studied the signalling properties of AspB10-insulin, an analog with enhanced affinity for the IGF-I receptor, in comparison to native insulin using primary human skeletal muscle cells. In myoblasts regular insulin and AspB10-insulin were equipotent in stimulating the IRS cascade, whereas this analog induced a significantly higher Shc phosphorylation. Phosphorylation of IRS-1 in response to insulin was inhibited equally by blocking either the insulin or the IGF-I receptor. IRS-1 activation by AspB10-insulin was only inhibited by blocking the IGF-I receptor. IRS-2 phosphorylation induced by both insulin and AspB10-insulin was nearly insensitive to blocking the insulin receptor, being predominantly mediated by the IGF-I receptor. We conclude that in myoblasts IRS-2, but not IRS-1, functions as preferred substrate for the IGF-I receptor. These data suggest a specific role for IRS-2 in growth and differentiation of human skeletal muscle.
Rakatzi
Irini
I
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
Stosik
Magdalene
M
Gromke
Tanja
T
Siddle
Kenneth
K
Eckel
Jürgen
J
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D014443:Tyrosine; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin