The mechanism of insulin-induced signal transduction mediated by the insulin receptor substrate family.
Distinct from other growth factor receptors, insulin and insulin-like growth factor-I (IGF-I) receptors phosphorylate endogenous substrates on tyrosine residues which in turn associate with the SH2 domain-containing proteins transducing signals to downstream pathways. Among the cellular substrates of insulin and IGF-I receptors, insulin receptor substrate (IRS)-1 has been shown to play an important role in mediating the actions of these hormones. Recently, several proteins with similar structures and different tissue distributions were cloned as IRS-2, -3 and -4. To study the roles of these IRSs in mediating insulin actions, we analyzed liver, muscle and adipocytes, the major targets of insulin actions, from IRS-1 null mice which we previously generated, and showed that: 1) insulin-stimulated activation of PI 3-kinase, mitogen-activated protein kinase and glucose transport were impaired in muscles from IRS-1 null mice which was in contrast to the grossly normal signaling and actions in livers from these mice; 2) the difference in the degree of insulin resistance in these two major insulin targets appeared to depend on the amount of tyrosine phosphorylation of IRS-2 compensating for IRS-1 deficiency; 3) insulin-induced activation of PI 3-kinase, glucose transport and GLUT4 translocation were impaired but not abolished in adipocytes from these mice in which IRS-3 was the major tyrosine-phosphorylated protein activating PI 3-kinase and at least partially mediating some residual insulin actions in the absence of IRS-1. These data suggest that the members of the IRS family redundantly regulate insulin actions in each target organ in a distinct fashion.
Kaburagi
Y
Y
The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Yamauchi
T
T
Yamamoto-Honda
R
R
Ueki
K
K
Tobe
K
K
Akanuma
Y
Y
Yazaki
Y
Y
Kadowaki
T
T
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000502:physiology; D009124:Muscle Proteins; D009132:Muscles / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin