Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway
Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway
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DOI：
10.1074/jbc.274.14.9351
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发表时间：
1999-04-02
影响因子：
4.8
通讯作者：
Roth, RA
中科院分区：
文献类型：
--
作者：
Li, JP;DeFea, K;Roth, RA
胰岛素受体底物1（IRS-1）的丝氨酸/苏氨酸磷酸化被认为是胰岛素信号传导的负调节因子。以往的研究表明，蛋白激酶C的这种负调节作用涉及丝裂原活化蛋白激酶和IRS-1中丝氨酸612的磷酸化。本研究比较了血小板衍生生长因子（PDGF）和蛋白激酶C激活剂内皮素-1（endothelin-1）对IRS-1的负调节作用。与内皮素-1相反，PDGF的抑制作用不需要丝裂原活化蛋白激酶或丝氨酸612的磷酸化。相反，IRS-1磷酸化结构域中的三个其他丝氨酸（丝氨酸632、662和731）是PDGF负调控所必需的。此外，发现PDGF激活的丝氨酸/苏氨酸激酶Akt抑制胰岛素信号传导。最后，雷帕霉素抑制了PDGF和Akt的负调节作用，雷帕霉素是Akt下游靶点之一的哺乳动物雷帕霉素靶蛋白（mTOR）的抑制剂。这些研究暗示磷脂酰肌醇3-激酶/Akt激酶级联是胰岛素信号级联的另一个负调节途径。
Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) has been implicated as a negative regulator of insulin signaling. Prior studies have indicated that this negative regulation by protein kinase C involves the mitogen-activated protein kinase and phosphorylation of serine 612 in IRS-1, In the present studies, the negative regulation by platelet-derived growth factor (PDGF) was compared with that induced by endothelin-1, an activator of protein kinase C. In contrast to endothelin-1, the inhibitory effects of PDGF did not require mitogen-activated protein kinase or the phosphorylation of serine 612. Instead, three other serines in the phosphorylation domain of IRS-1 (serines 632, 662, and 731) were required for the negative regulation by PDGF. In addition, the PDGF-activated serine/threonine kinase called Akt was found to inhibit insulin signaling. Moreover, this inhibition required the same IRS-1 serine residues as the inhibition by PDGF, Finally, the negative regulatory effects of PDGF and Akt were inhibited by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), one of the downstream targets of Akt, These studies implicate the phosphatidylinositol 3-kinase/Akt kinase cascade as an additional negative regulatory pathway for the insulin signaling cascade.