Analysis of negative-feed back mechanism through mTOR pathway in insulin action.

mTOR 通路在胰岛素作用中的负反馈机制分析。

• 批准号: 15590932
• 负责人: KOBAYASHI Masashi
• 金额: $ 2.24万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590932/
• 关键词: IRS-1; serine kinase; JNK; IL-1; IKK; proteasome; インスリン抵抗性; negative feedback; セリン燐酸化; mTOR; プロテアソーム; rapamycin; anisomycin

1)Roles of mTOR and INK in insulin or anisomycin-induced IRS-1 serine phosphorylation.In 3T3-L1 adipocytes, insulin-induced phosphorylation of IRS-1 on Ser 307, ser 612, and Ser 636/639 was reduced by rapamycin, and was further inhibited by the combination with JNK inhibitor, SP 600125. Anisomycin-induced phosphorylation on the same residues was inhibited both rapamycin and SP 600125. Unlike insulin, anisomycin failed to elicit translocation or degradation of IRS-1. Therefore, mTOR and JNK pathways play the same IRS-1 serine phosphorylation, but are different in IRS-1 translocation and degradation.2)IL-1α and IRS-1 serine phosphorylation.IRS-1 was transiently phosphorylated on some serine residues around 15min after IL-1 stimulation, when several serine kinases, IKK, JNK, ERK, and p70S6K were activated. Tyrosine phosphorylation of IRS-1 was recovered only by IKK inhibitor or JNK inhibotor, suggesting the specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited by IL-1. Akt phosphorylation was synergistically inhibited by IL-1 in the presence IL-6. Thus, short term IL-1 treatment transiently causes insulin resistance at the level of IRS-1 with its serine phosphorylation. IL1 may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.

1)mTOR和JNK在胰岛素或茴香霉素诱导的IRS-1丝氨酸磷酸化中的作用在3 T3-L1脂肪细胞中，胰岛素诱导的IRS-1在Ser 307、Ser 612和Ser 636/639上的磷酸化被雷帕霉素减少，并且被JNK抑制剂SP 600125组合进一步抑制。雷帕霉素和SP 600125均抑制了茴香霉素诱导的相同残基的磷酸化。与胰岛素不同，茴香霉素不能引起IRS-1的移位或降解。2）IL-1α和IRS-1丝氨酸磷酸化：IL-1 α刺激后15 min左右，IRS-1在某些丝氨酸残基上发生短暂磷酸化，此时IKK、JNK、ERK和p70 S6 K等多种丝氨酸激酶被激活。IRS-1的酪氨酸磷酸化仅被IKK抑制剂或JNK抑制剂恢复，表明这两种激酶特异性参与。胰岛素刺激的Akt磷酸化和2-脱氧葡萄糖摄取不受IL-1抑制。Akt磷酸化在IL-6存在下被IL-1协同抑制。因此，短期IL-1治疗在IRS-1及其丝氨酸磷酸化水平上瞬时引起胰岛素抵抗。在其他细胞因子如IL-6的存在下，IL-1可抑制IRS-1下游的胰岛素信号传导。

项目成果

Protein phosphatase 2C alpha as a positive regulator of insulin sensitivity through direct activation of phospharidylinositol 3-kinase in 3T3-L1 adipocytes.

蛋白磷酸酶 2C α 通过直接激活 3T3-L1 脂肪细胞中的磷脂酰肌醇 3-激酶，作为胰岛素敏感性的正调节剂。

• 发表时间: 2004
• 期刊: J Biol Chem 279
• 作者: Yoshizaki T.;Maegawa H.;Egawa K.;Ugi S.;Nishino Y.;Imamura T.;Kobayashi M.;Tamura S.;Olefsky J.M.;Kashiwagi A.
• 通讯作者: Kashiwagi A.

SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes

• DOI: 10.1074/jbc.m311534200
• 发表时间: 2004-04-09
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Sasaoka, T;Wada, T;Kobayashi, M
• 通讯作者: Kobayashi, M

Dual role of src homology domain 2-containing inositol phosphatase 2 in the regulation of platelet-derived growth factor and insulin-like growth factor 1 signaling in rat vascular smooth muscle cells.

含有 src 同源结构域 2 的肌醇磷酸酶 2 在调节大鼠血管平滑肌细胞中血小板衍生生长因子和胰岛素样生长因子 1 信号传导中的双重作用。

• 发表时间: 2003
• 期刊: Endocrinology 145
• 作者: Sasaoka T.;Kikuchi K.;Wada T.;Sato A.et al.Kobayashi M.
• 通讯作者: Sato A.et al.Kobayashi M.

Nakamura N., Hamazaki T., Johkaji H., Minami S., Yamazaki K., Sato A., Sawazaki S., Yamazaki K., Sato A., Sawazaki S., Urakaze M., Kobayashi M., Osawa H., Yamabe H., Okumura K.: "Effects of cilostazol on serum lipid concentrations and plasma fatty acid co

中村 N.、滨崎 T.、Johkaji H.、南 S.、山崎 K.、佐藤 A.、泽崎 S.、山崎 K.、佐藤 A.、泽崎 S.、浦风 M.、小林 M.、大泽 H

Impact of src homology 2-containing inositol 5'-phosphatase 2 on the regulation of insulin signaling leading to protein synthesis in 3T3-L1 adipocytes cultured with excess amino acids.

含有 src 同源性 2 的肌醇 5-磷酸酶 2 对胰岛素信号传导的影响，导致用过量氨基酸培养的 3T3-L1 脂肪细胞中的蛋白质合成。

• 发表时间: 2004
• 期刊: Endocrinology 145
• 作者: Murakami S.;Sasaoka T.;Wada T.;Fukui K.;Nagira K.;Ishihara H.;Usui I.;Kobayashi M.
• 通讯作者: Kobayashi M.