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SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling

机译：SU6656，一种选择性的Src家族激酶抑制剂，用于探测生长因子信号

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The use of small-molecule inhibitors to study molecular components of cellular signal transduction pathways provides a means of analysis complementary to currently used techniques, such as antisense, dominant-negative (interfering) mutants and constitutively activated mutants. We have identified and characterized a small-molecule inhibitor, SU6656, which exhibits selectivity for Src and other members of the Src family. A related inhibitor, SU6657, inhibits many kinases, including Src and the platelet-derived growth factor (PDGF) receptor. The use of SU6656 confirmed our previous findings that Src family kinases are required for both Myc induction and DNA synthesis in response to PDGF stimulation of NIH 3T3 fibroblasts. By comparing PDGF-stimulated tyrosine phosphorylation events in untreated and SU6656-treated cells, we found that some substrates (for example, c-Cbl, and protein kinase C δ) were Src family substrates whereas others (for example, phospholipase C-γ) were not. One protein, the adaptor Shc, was a substrate for both Src family kinases (on tyrosines 239 and 240) and a distinct tyrosine kinase (on tyrosine 317, which is perhaps phosphorylated by the PDGF receptor itself). Microinjection experiments demonstrated that a Shc molecule carrying mutations of tyrosines 239 and 240, in conjunction with an SH2 domain mutation, interfered with PDGF-stimulated DNA synthesis. Deletion of the phosphotyrosine-binding domain also inhibited synthesis. These inhibitions were overcome by heterologous expression of Myc, supporting the hypothesis that Shc functions in the Src pathway. SU6656 should prove a useful additional tool for further dissecting the role of Src kinases in this and other signal transduction pathways.
机译：使用小分子抑制剂研究细胞信号转导途径的分子成分，提供了一种与当前使用的技术互补的分析手段，例如反义，显性负（干扰）突变体和组成性激活突变体。我们已经鉴定和表征了一种小分子抑制剂SU6656，它对Src和Src家族的其他成员具有选择性。相关的抑制剂SU6657抑制许多激酶，包括Src和血小板衍生的生长因子（PDGF）受体。 SU6656的使用证实了我们先前的发现，即Myc诱导和DNA合成均需要Src家族激酶来响应PDGF刺激NIH 3T3成纤维细胞。通过比较PDGF刺激的未经处理和经SU6656处理的细胞中酪氨酸磷酸化事件，我们发现某些底物（例如c-Cbl和蛋白激酶Cδ）是Src家族底物，而其他底物（例如磷脂酶C-γ）不是。一种蛋白质，衔接子Shc，是Src家族激酶（在酪氨酸239和240上）和独特的酪氨酸激酶（在酪氨酸317上，可能被PDGF受体自身磷酸化）的底物。显微注射实验表明，带有酪氨酸239和240突变的Shc分子与SH2域突变一起干扰了PDGF刺激的DNA合成。磷酸酪氨酸结合结构域的删除也抑制了合成。 Myc的异源表达克服了这些抑制作用，支持了Shc在Src途径中起作用的假说。 SU6656应该被证明是进一步剖析Src激酶在此和其他信号转导途径中的作用的有用的附加工具。

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