1996 Fiscal Year Final Research Report Summary
Mechanism of insulin action and its disorder
| Project/Area Number |
06404038
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | Kobe University |
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Principal Investigator |
KASUGA Masato Kobe University School of Medicine, Professor, 医学部, 教授 (50161047)
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| Co-Investigator(Kenkyū-buntansha) |
MATOZAKI Takashi Kobe University School of Medicine, Assistant Professor, 医学部附属病院, 助手 (80252782)
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| Project Period (FY) |
1994 – 1995
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| Keywords | IRS-1 / PI 3-kinase / Grb2・Sos complex / SH PTP-2 / glucose transporters / Ras / Ras |
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| Research Abstract |
Non-insulin-dependent diabetes mellitus (NIDDM) is common disorder of glucose homeostasis affecting -5% of the general population. NIDDM is characterized by defects in the insulin secretion from pancreatic beta-cells and/or the insulin action in peripheral tissues.
Insulin treatment of various intact cells causes rapid tyrosine phosphorylation of a high molecular weight protein (Mr=16,000-185,000) designated pp185. A cDNA encoding pp185 was isolated and the predicted protein was named insulin receptor substrate-1 (IRS-1). Tyrosinphosphorylated IRS-1 binds several signaling molecules, including the 85kDa subunit of phosphoinositide (PI) 3-kinase, Grb2・Sos complex and SH PTP-2 via their Src homology 2 (SH2) domain. To identify new candidate genes for NIDDM,we overexpressed the dominant negative type of 85kDa subunit of PI 3-kinase, Grb2・Sos complex and SH PTP-2 in Chinese hamster ovary cells overexpressing the insulin receptor. Overexpression of dominant negative type of these signaling molecules revealed that PI 3-kinase involves in insulin-stimulated glucose uptake and translocation of glucose transporters, but not in Ras activation. On the other hand, Grb2 and SH PTP-2 involves in insulin-stimulated Ras activation, but not in insulin-stimulated glucose uptake and translocation of glucose transporters. These data suggest that PI 3-kinase is a new candidate gene for NIDDM.
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[Publications] Sakaue, H., Hara, K., Noguchi, T., Matozaki, T., Kotani, K., Ogawa, W., Yonezawa, K.: "Waterfield, M.D.and Kasuga, M.Ras-independent and wortmannin-sensitive activation of glycogen synthase by insulin in CHO cells." J.Biol.Chem.270. 11304-11309 (1995)
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「研究成果報告書概要(欧文)」より
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[Publications] Noguchi, T., Matozaki, T., Horita, K., Fujioka, Y.and Kasuga, M.: "Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology-2 domains, in insulinstimulated Ras activation." Mol.Cell.Biol.14. 6674-6682 (1994)
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「研究成果報告書概要(欧文)」より
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[Publications] Hara, K., Yonezawa, K., Sakaue, H., Ando, A., Kotani, K., Kitamura, Y., Ueda, H., Stephens, L., Jackson, T.R., Hawkins, P.T., Dhand, R., Clark, A.E., Holman, G.D., Waterfield, M.D.and Kasuga, M.: "Phosphoinositide 3-kinase activity is required for insulin-stimulated glucose transport but not for ras activation in CHO cells." Proc.Natl.Acad.Sci.USA.91. 7415-7419 (1994)
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[Publications] Ando, A., Yonezawa, K., Gout, I., Nakata, T., Ueda, H., Hara, K., Kitamura, Y., Noda, Y., Takenawa, T., Hirokawa, N., Waterfield, M.D.and Kasuga, M.: "A complex of GRB2-dynamin binds to tyrosine-phosphorylated insulin receptor substrate-1 after insulin treatment." EMBO J.13. 3033-3038 (1994)
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[Publications] Kotani, K., Yonezawa, K., Hara, K., Ueda, H., Ido, Y., Sakaue, H., Ando, A., Chavanieu, A., Calas, B., Grigorescu, F., Nishiyama, M., Waterfield, M.D.and Kasuga, M.: "Involvement of phosphoinositide 3-kinase in insulin or IGF-1-induced membrane ruffling." EMBO J.13. 2313-2321 (1994)
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[Publications] Uchida, T., Matozaki, T., Noguchi, T., Yamao, T., Horita, K., Suzuki, T., Fujioka, Y., Sakamoto, C.and Kasuga, M.: "Insulin stimulates the phosphorylation of Tyr^<538> and the catalytic activity of PTP1C,a protein tyrosine phosphatase with Src-Homology-2 domains." J.Biol.Chem.269. 12220-12228 (1994)
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[Publications] Kishimoto, M., Hashiramoto, M., Yonezawa, K., Shii, K., Kazumi, T.and Kasuga, M.: "Substitution of glutamine for arginine 1131 : A newly-identified mutation in the catalytic loop of the tyrosine kinase domain of the human insulin receptor." J.Biol.Chem.269. 11349-11355 (1994)
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[Publications] Yonezawa, K., Ando, A., Kaburagi, Y., Yamamoto-Honda, R., Kitamura, T., Hara, K., Nakafuku, M., Okabayashi, Y., Kadowaki, T., Kaziro, Y.and Kasuga, M.: "Signal transduction pathways from insulin receptors to Ras : Analysis by mutant insulin receptors." J.Biol.Chem.269. 4634-4640 (1994)
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