Molecular mechanism of IRS-1 degradation by PLGγ and PP2C

PLGγ和PP2C降解IRS-1的分子机制

• 批准号: 14571089
• 负责人: EGAWA Katsuya
• 金额: $ 2.18万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571089/
• 关键词: PLCg; PP2C; IRS-1 degradation; adenovirus

We found that U73122,which was phospholioase C(PLC) inhibitor, blocked insulin-induced glucose uptake in 3T3-L1 adipocytes. Moreover, overexpression of PLCγ stimulated glucose uptake without insulin stimulation in a dose dependent manner. Overexpression of PLCγ did not affect phosphorylation of Akt, but enhanced phosphorylation of atypical PKC. Thus, it suggests that PLCγ stimulates gluxoce uptake through activation of atypical PKC.Overexpression of protein phosphatase 2C(PP2C) caused dephosphorylation of serine residue of p85 of PI 3-kinase, and positively regulated insulin signaling. On the other hand, overexpression of PP2C accelerated insulin-stimulated IRS-1 degradation. When we suppressed PP2C protein expression by sRNA interference method, insulin-induced IRS-1 degradation was inhibited. Moreover, PP2C-induced IRS-1 degradation was completely inhibited by lactasistine treatment, which was proteasome inhibitor. PI 3-kinase inhibitor, wortmannin, also suppressed it, partially. Taken together, PP2C has both positive and negative effects on insulin signaling through PI 3-kinase pathway.

我们发现，磷脂酶C(PLC)抑制剂U73122可以阻断胰岛素诱导的3T3-L1脂肪细胞的葡萄糖摄取。此外，在没有胰岛素刺激的情况下，PLCγ的过表达以剂量依赖的方式刺激葡萄糖摄取。过表达PLCγ不影响Akt的磷酸化，但促进非典型蛋白激酶C的磷酸化。因此，提示PLCγ通过激活非典型PKC刺激谷氨酸摄取，蛋白磷酸酶2C(PP2C)的过度表达导致PI3K的P85丝氨酸残基去磷酸化，并正向调节胰岛素信号转导。另一方面，PP2C的过表达加速了胰岛素刺激的IRS-1的降解。当我们通过SRNA干扰方法抑制PP2C蛋白的表达时，胰岛素诱导的IRS-1降解被抑制。蛋白酶体抑制剂Lactasistine可完全抑制PP2C诱导的IRS-1降解。PI 3-激酶抑制剂Wortmannin也部分抑制了它的表达。综上所述，PP2C通过PI3K途径对胰岛素信号传导既有积极的影响，也有消极的影响。

项目成果

Protein phosphatase 2A negatively regulates insulin's metabolic signaling psthway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes.

蛋白磷酸酶 2A 通过抑制 3T3-L1 脂肪细胞中的 Akt（蛋白激酶 B）活性来负调节胰岛素的代谢信号通路。

• 发表时间: 2004
• 期刊: Mol Cell Biol 24
• 作者: Ugi S;Imamura T;Maegawa H;Egawa K;Yoshizaki T;Shi K;Obata T;Ebina Y;Kashiwagu A;Olefsky JM.
• 通讯作者: Olefsky JM.

Protein Phosphatase 2A Negatively Regulates Insulin's Metabolic Signaling Pathway by Inhibiting Akt (Protein Kinase B) Activity in 3T3-L1 Adipocytes

• DOI: 10.1128/mcb.24.19.8778-8789.2004
• 发表时间: 2004-10
• 期刊: Molecular and Cellular Biology
• 影响因子: 5.3
• 作者: S. Ugi;T. Imamura;H. Maegawa;K. Egawa;Takeshi Yoshizaki;K. Shi;T. Obata;Y. Ebina;A. Kashiwagi;J. Olefsky

Protein phosphatase 2Calpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3 kinase in 3T3-L1 adipocytes

蛋白磷酸酶 2Calpha 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. et al.
• 通讯作者: T. et al.

Sekine O, Nishio Y, Egawa K et al.: "Insulin activates CCAAT/enhancer binding proteins and proinflammatory gene expression through the phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells."J Biol Chem. 277. 36631-36639 (2002)

Sekine O、Nishio Y、Egawa K 等人：“胰岛素通过血管平滑肌细胞中的磷脂酰肌醇 3-激酶途径激活 CCAAT/增强子结合蛋白和促炎基因表达。”J Biol Chem。

Mechanism for differential effect of protein-tyrosine phosphatase IB on Akt versus mitogen-activated protein kinase in 3T3-L1 adipocytes.

蛋白酪氨酸磷酸酶 IB 对 3T3-L1 脂肪细胞中 Akt 与丝裂原激活蛋白激酶的差异作用机制。

• 发表时间: 2002
• 期刊: Endocrinology 143
• 作者: Shimizu S;Maegawa H;Egawa K;Shi K;Bryer-Ash M;Kashiwagi A.
• 通讯作者: Kashiwagi A.