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首页> 外文期刊>Molecular and Cellular Biology >Regulation of c-Fes Tyrosine Kinase and Biological Activities by N-Terminal Coiled-Coil Oligomerization Domains
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Regulation of c-Fes Tyrosine Kinase and Biological Activities by N-Terminal Coiled-Coil Oligomerization Domains

机译：N末端螺旋线圈低聚域对c-Fes酪氨酸激酶和生物活性的调节

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The cytoplasmic protein-tyrosine kinase Fes has been implicated in cytokine signal transduction, hematopoiesis, and embryonic development. Previous work from our laboratory has shown that active Fes exists as a large oligomeric complex in vitro. However, when Fes is expressed in mammalian cells, its kinase activity is tightly repressed. The Fes unique N-terminal sequence has two regions with strong homology to coiled-coil-forming domains often found in oligomeric proteins. Here we show that disruption or deletion of the first coiled-coil domain upregulates Fes tyrosine kinase and transforming activities in Rat-2 fibroblasts and enhances Fes differentiation-inducing activity in myeloid leukemia cells. Conversely, expression of a Fes truncation mutant consisting only of the unique N-terminal domain interfered with Rat-2 fibroblast transformation by an activated Fes mutant, suggesting that oligomerization is essential for Fes activation in vivo. Coexpression with the Fes N-terminal region did not affect the transforming activity of v-Src in Rat-2 cells, arguing against a nonspecific suppressive effect. Taken together, these findings suggest a model in which Fes activation may involve coiled-coil-mediated interconversion of monomeric and oligomeric forms of the kinase. Mutation of the first coiled-coil domain may activate Fes by disturbing intramolecular coiled-coil interaction, allowing for oligomerization via the second coiled-coil domain. Deletion of the second coiled-coil domain blocks fibroblast transformation by an activated form of c-Fes, consistent with this model. These results provide the first evidence for regulation of a nonreceptor protein-tyrosine kinase by coiled-coil domains.
机译：细胞质蛋白酪氨酸激酶Fes与细胞因子信号转导，造血作用和胚胎发育有关。我们实验室的先前工作表明，活性Fes在体外以大型寡聚复合物的形式存在。但是，当Fes在哺乳动物细胞中表达时，其激酶活性被严格抑制。 Fes独特的N端序列具有两个与在寡聚蛋白中经常发现的卷曲螺旋形成域具有高度同源性的区域。在这里，我们显示破坏或删除第一个螺旋线圈域上调大鼠2成纤维细胞中的Fes酪氨酸激酶和转化活性，并增强了髓样白血病细胞中Fes的分化诱导活性。相反，仅由独特的N末端结构域组成的Fes截短突变体的表达干扰了激活的Fes突变体对Rat-2成纤维细胞转化的影响，这表明寡聚化对于体内Fes激活至关重要。与Fes N端区域共表达不会影响v-Src在Rat-2细胞中的转化活性，这归因于非特异性抑制作用。综上所述，这些发现提出了一个模型，其中Fes激活可能涉及线圈的螺旋形式的单体和寡聚形式的相互转化。第一卷曲螺旋结构域的突变可通过干扰分子内的卷曲螺旋相互作用而激活Fes，从而允许经由第二卷曲螺旋结构域的寡聚。与该模型一致，第二个卷曲螺旋结构域的缺失通过活化形式的c-Fes阻止了成纤维细胞转化。这些结果为通过卷曲螺旋结构域调节非受体蛋白酪氨酸激酶提供了第一个证据。

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