SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes
SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes
复制标题
DOI：
10.1007/s001250100645
复制
发表时间：
2001-10-01
期刊：
影响因子：
8.2
通讯作者：
Kobayashi, M
中科院分区：
文献类型：
--
作者：
Sasaoka, T;Hori, H;Kobayashi, M
目的/假设。PI 3-激酶产生的PI（3，4，5）P3是胰岛素代谢作用的关键介质。我们最近克隆了大鼠SHIP 2 cDNA，它在胰岛素靶组织中大量表达。在此，我们阐明了SHIP 2对PI（3，4，5）P3具有5 '-磷酸酶活性在骨骼肌胰岛素信号传导中的作用。通过腺病毒介导的基因转移方法，将野生型（WT）-SHIP 2和5 '-磷酸酶缺陷型（AIP）SHIP 2分别表达于L 6肌管中，研究SHIP 2在胰岛素诱导的糖原合成中的作用。胰岛素信号传导的早期事件，包括胰岛素受体和IRS-1的酪氨酸磷酸化，IRS-1与p85亚基的关联，以及PI 3-激酶活性不受WT-和Delta IP-SHIP 2表达的影响。尽管PI（3，4，5）P3和PI（3，4）P2已知可能在体外激活PI 3-激酶Akt的下游分子，但WT-SHIP 2的过表达抑制胰岛素诱导的Akt磷酸化和激活。相反，Akt活性通过Delta IP-SHIP 2的表达而增加。位于Akt下游的GSK 3 β是进一步传递胰岛素信号用于骨骼肌糖原合成的重要分子。与Akt、胰岛素诱导的磷酸化和GSK 3 β失活的结果一致，随后的糖原合成酶的激活和糖原合成通过WT-SHIP 2的表达而减少，而这些事件通过Delta IP-SHIP 2的表达而增加。我们的研究结果表明，SHIP 2通过5 '-磷酸酶活性在胰岛素信号传导中起负调节作用，并且PI（3，4，5）P3而不是PI（3，4）P2对于体内调节胰岛素诱导的Akt活化导致L 6肌管中糖原合成是重要的。
Aims/hypothesis. PI(3,4,5)P3 produced by PI3-kinase seems to be a key mediator for insulin's metabolic actions. We have recently cloned rat SHIP2 cDNA which is abundantly expressed in target tissues of insulin. Here, we clarify the role of SHIP2 possessing 5'-phosphatase activity toward PI(3,4,5)P3 in insulin signalling in the skeletal muscle.Methods. The role of SHIP2 in insulin-induced glycogen synthesis was studied by expressing wild-type (WT)-SHIP2 and a 5'-phosphatase defective (AIP)SHIP2 into L6 myotubes by means of adenovirus mediated gene transfer.Results. The early events of insulin signalling including tyrosine phosphorylation of the insulin receptor and IRS-1, IRS-1 association with the p85 subunit, and PI3-kinase activity were not affected by expression of WT- and Delta IP-SHIP2. Although PI(3,4,5)P3 and PI(3,4)P2 are known to possibly activate a downstream molecule of PI3-kinase Akt in vitro, overexpression of WT-SHIP2 inhibited insulin-induced phosphorylation and activation of Akt. Conversely, Akt activity was increased by expression of Delta IP-SHIP2. GSK3 beta located downstream of Akt is an important molecule to further transmit insulin signal for glycogen synthesis in skeletal muscles. In accordance with the results of Akt, insulin-induced phosphorylation and inactivation of GSK3 beta, subsequent activation of glycogen synthase and glycogen synthesis were decreased by expression of WT-SHIP2, whereas these events were increased by expression of Delta IP-SHIP2.Conclusion/interpretation. Our results indicate that SHIP2 plays a negative regulatory role via the 5'-phosphatase activity in insulin signalling, and that PI(3,4,5)P3 rather than PI(3,4)P2 is important for in vivo regulation of insulin-induced Akt activation leading to glycogen synthesis in L6 myotubes.