Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene.
The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). After tyrosine phosphorylation at several sites, IRS-1 binds to and activates phosphatidylinositol-3'-OH kinase (PI(3)K) and several other proteins containing SH2 (Src-homology 2) domains. To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. These mice had no IRS-1 and showed no evidence of IRS-1 phosphorylation or IRS-1-associated PI(3)K activity. They also had a 50 per cent reduction in intrauterine growth, impaired glucose tolerance, and a decrease in insulin/IGF-1-stimulated glucose uptake in vivo and in vitro. The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.
Araki
E
E
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215.
Lipes
M A
MA
Patti
M E
ME
Brüning
J C
JC
Haag
B
B
Johnson
R S
RS
Kahn
C R
CR
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D006128:Growth / Q000502:physiology; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000172:deficiency / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019000:Phosphotyrosine; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D019000:Phosphotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)