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首页> 外文期刊>Molecular and Cellular Biology >Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase.
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Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase.

机译：SH2和SH3域在调节Abl酪氨酸激酶中作用的诱变分析。

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We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inhibitory activity is extremely position sensitive, because mutants in which the position of the SH3 domain within the protein is subtly altered are fully transforming. In contrast to the case in vivo, the SH3 domain has no effect on the in vitro kinase activity of the purified protein. These results are consistent with a model in which the SH3 domain binds a cellular inhibitory factor, which in turn must physically interact with other parts of the kinase. Unlike the SH3 domain, the SH2 domain is required for transforming activity of activated Abl alleles. We demonstrate that SH2 domains from other proteins (Ras-GTPase-activating protein, Src, p85 phosphatidylinositol 3-kinase subunit, and Crk) can complement the absence of the Abl SH2 domain and that mutants with heterologous SH2 domains induce altered patterns of tyrosine-phosphorylated proteins in vivo. The positive function of the SH2 domain is relatively position independent, and the effect of multiple SH2 domains appears to be additive. These results suggest a novel mechanism for regulation of tyrosine kinases in which the SH2 domain binds to, and thereby enhances the phosphorylation of, a subset of proteins phosphorylated by the catalytic domain. Our data also suggest that the roles of the SH2 and SH3 domains in the regulation of Abl are different in several respects from the roles proposed for these domains in the closely related Src family of tyrosine kinases.
机译：我们已经使用体外诱变来详细检查两个模块蛋白结构域SH2和SH3在调节Abl酪氨酸激酶中的作用。如先前所示，SH3结构域抑制体内正常非转化c-Abl产物的固有转化活性。我们在这里显示出这种抑制活性对位置极为敏感，因为其中蛋白质内SH3结构域的位置被微妙改变的突变体已完全转化。与体内情况相反，SH3结构域对纯化蛋白的体外激酶活性没有影响。这些结果与其中SH3结构域结合细胞抑制因子的模型是一致的，该模型又必须与激酶的其他部分发生物理相互作用。与SH3结构域不同，SH2结构域是转化活化的Abl等位基因的活性所必需的。我们证明了其他蛋白（Ras-GTPase激活蛋白，Src，p85磷脂酰肌醇3激酶亚基和Crk）的SH2结构域可以弥补Abl SH2结构域的缺失，并且具有异源SH2结构域的突变体会诱导酪氨酸-体内磷酸化蛋白。 SH2域的正功能是相对位置无关的，并且多个SH2域的作用似乎是加和的。这些结果提示了一种新型的酪氨酸激酶调节机制，其中SH2结构域与被催化结构域磷酸化的一部分蛋白质结合，从而增强了其磷酸化。我们的数据还表明，SH2和SH3结构域在Abl调节中的作用在几个方面与在紧密相关的酪氨酸激酶Src家族中针对这些结构域的作用有所不同。

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