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首页> 外文期刊>Molecular and Cellular Biology >Cellular effects of phosphotyrosine-binding domain inhibitors on insulin receptor signaling and trafficking.
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Cellular effects of phosphotyrosine-binding domain inhibitors on insulin receptor signaling and trafficking.

机译：磷酸酪氨酸结合域抑制剂对胰岛素受体信号传导和运输的细胞作用。

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Shc and insulin receptor substrate 1 (IRS-1) are cytoplasmic substrates of tyrosine kinase receptors that engage, localize, and activate downstream SH2 enzymes. Each contains a phosphotyrosine-binding (PTB) domain that is structurally unrelated to SH2 domains. We have designed high-affinity, cellular inhibitors of the Shc PTB domain by incorporating nonnatural, phosphatase-resistant amino acids into short peptides. None of the inhibitors bind the IRS-1 PTB domain, consistent with distinct specificities for domains. The best inhibitor of the Shc domain was introduced by electroporation into Rat1 fibroblasts that express human insulin receptors. Insulin-stimulated phosphorylation of Shc was inhibited, with no effect on IRS-1, and downstream effects on mitogen-activated protein kinase and DNA synthesis were both inhibited. The PTB domain inhibitor had less influence on epidermal growth factor-induced effects and essentially no impact on serum- or phorbol ester-induced effects. The inhibitor did not affect insulin internalization and its degradation. We conclude that the PTB domain of Shc is critical for its phosphorylation by the insulin receptor, that Shc is an important mediator of insulin's mitogenic effects, and that Shc is not central to insulin receptor cycling in these cells. PTB domains can be inhibited selectively in cells and represent potential targets for drug discovery.
机译：Shc和胰岛素受体底物1（IRS-1）是酪氨酸激酶受体的细胞质底物，它们参与，定位和激活下游SH2酶。每个都包含磷酸酪氨酸结合（PTB）域，该域在结构上与SH2域无关。我们设计了Shc PTB域的高亲和力细胞抑制剂，方法是将非天然磷酸酶抗性氨基酸掺入短肽中。没有抑制剂与IRS-1 PTB结构域结合，这与结构域的独特特异性相一致。 Shc域的最佳抑制剂通过电穿孔引入表达人胰岛素受体的Rat1成纤维细胞中。胰岛素刺激的Shc磷酸化被抑制，对IRS-1没有影响，而对有丝分裂原激活的蛋白激酶和DNA合成的下游影响均被抑制。 PTB结构域抑制剂对表皮生长因子诱导的作用影响较小，而对血清或佛波醇酯诱导的作用基本上没有影响。该抑制剂不影响胰岛素内在化及其降解。我们得出结论，Shc的PTB结构域对于胰岛素受体的磷酸化至关重要，Shc是胰岛素促有丝分裂作用的重要介质，并且Shc在这些细胞中对胰岛素受体循环并不重要。可以在细胞中选择性抑制PTB结构域，并代表药物发现的潜在靶标。

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