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首页> 外文期刊>Molecular and Cellular Biology >Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70.
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Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70.

机译：通过ZAP-70功能获得性突变增强淋巴细胞反应性。

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The protein tyrosine kinase ZAP-70 plays an essential role in T-cell activation and development. After T-cell receptor stimulation, ZAP-70 is associated with the receptor and is phosphorylated on many tyrosine residues, including tyrosine 292 (Y-292), in the region between the C-terminal SH2 domain and the kinase domain (interdomain B). Here we show that a mutation of Y-292 (292F) or deletion of interdomain B enhanced the ability of ZAP-70 to reconstitute B-cell receptor stimulation-dependent NF-AT induction in a B-cell line deficient in Syk. In contrast, in a T-cell line, expression of 292F led to basal NF-AT induction independent of T-cell receptor stimulation. These results demonstrate that the role of Y-292 is to negatively regulate the function of ZAP-70 in lymphocytes. This appears to be a dominant function of interdomain B because deletion of most of interdomain B also resulted in a mutant of ZAP-70 with enhanced ability to reconstitute Syk-deficient DT-40 B cells. Since our biochemical studies did not reveal an effect of the 292F mutation on either the kinase activity of ZAP-70 or on the ability of ZAP-70 to bind to the receptor, we propose a model in which Y-292 interacts with an inhibitory protein to negatively regulate ZAP-70 function.
机译：蛋白质酪氨酸激酶ZAP-70在T细胞活化和发育中起重要作用。在T细胞受体刺激后，ZAP-70与受体结合，并在C端SH2结构域和激酶结构域（结构域B）之间的许多酪氨酸残基上被磷酸化，包括酪氨酸292（Y-292）。 。在这里，我们显示Y-292（292F）的突变或域间B的缺失增强了ZAP-70在缺乏Syk的B细胞系中重建B细胞受体刺激依赖性NF-AT诱导的能力。相反，在T细胞系中，292F的表达导致独立于T细胞受体刺激的基础NF-AT诱导。这些结果证明Y-292的作用是负调节淋巴细胞中ZAP-70的功能。这似乎是域间B的主要功能，因为大部分域间B的缺失也导致ZAP-70突变体具有增强的Syk缺陷DT-40 B细胞重构能力。由于我们的生化研究并未揭示292F突变对ZAP-70的激酶活性或ZAP-70与受体结合的能力的影响，因此我们提出了一种模型，其中Y-292与抑制蛋白相互作用负调节ZAP-70的功能。

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