title: Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes.
abstract: In muscle and fat, glucose transport occurs through the translocation of GLUT4 from an intracellular pool to the cell surface. Phosphatidylinositol (PI) 3-kinase has been shown to be required in this process. Insulin is thought to activate this enzyme by stimulating its association with tyrosine-phosphorylated proteins such as insulin receptor substrate (IRS)-1, IRS-2, Grb2-associated binder-1, and pp60. To study the role of these endogenous substrates in glucose transport, we analyzed adipocytes from IRS-1 null mice that we previously generated (Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S., Sekihara, H., Yoshioka, S., Horikoshi, H., Furuta, Y. , Ikawa, Y., Kasuga, M., Yazaki Y., and Aizawa S. (1994) Nature 372, 182-186). In adipocytes from these mice, we showed that: 1) insulin-induced PI 3-kinase activity in the antiphosphotyrosine immunoprecipitates was 54% of wild-type; 2) pp60 was the major tyrosine-phosphorylated protein that associated with PI 3-kinase, whereas tyrosine phosphorylaion of IRS-2 as well as its association with this enzyme was almost undetectable; and 3) glucose transport and GLUT4 translocation at maximal insulin stimulation were decreased to 52 and 68% of those from wild-type. These data suggest that both IRS-1 and pp60 play a major role in insulin-induced glucose transport in adipocytes, and that pp60 is predominantly involved in regulating this process in the absence of IRS-1.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kaburagi
authors.forename: S
authors.initials: S
authors.lastname: Satoh
authors.forename: H
authors.initials: H
authors.lastname: Tamemoto
authors.forename: R
authors.initials: R
authors.lastname: Yamamoto-Honda
authors.forename: K
authors.initials: K
authors.lastname: Tobe
authors.forename: K
authors.initials: K
authors.lastname: Veki
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: E
authors.initials: E
authors.lastname: Kono-Sugita
authors.forename: H
authors.initials: H
authors.lastname: Sekihara
authors.forename: S
authors.initials: S
authors.lastname: Aizawa
authors.forename: S W
authors.initials: SW
authors.lastname: Cushman
authors.forename: Y
authors.initials: Y
authors.lastname: Akanuma
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000502:physiology*; D007329:Insulin Antagonists / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D019000:Phosphotyrosine / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D051275:Glucose Transporter Type 4; D007328:Insulin; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C495693:Slc2a4 protein, mouse; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D005947:Glucose; D000077191:Wortmannin