Jak1 Has a Dominant Role over Jak3 in Signal Transduction through γc-Containing Cytokine Receptors
Jak1 Has a Dominant Role over Jak3 in Signal Transduction through γc-Containing Cytokine Receptors
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DOI：
10.1016/j.chembiol.2011.01.012
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发表时间：
2011-03-25
影响因子：
--
通讯作者：
Zerwes, Hans-Guenter
中科院分区：
文献类型：
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作者：
Haan, Claude;Rolvering, Catherine;Zerwes, Hans-Guenter
Jak 3的遗传缺陷导致通过共同γ链（γ c）的信号转导的废除，从而导致免疫缺陷，这表明特异性抑制Jak 3激酶可能导致免疫抑制。Jak 1与Jak 3通过含γ c受体进行信号传导。出乎意料的是，Jak 3选择性抑制剂在消除STAT 5磷酸化方面的效率低于泛Jak抑制剂。因此，我们使用重建系统探索了Jak 1和Jak 3激酶功能在信号传导中的作用。激酶失活的Jak 1而非激酶失活的Jak 3的存在导致STAT 5磷酸化的完全消除。ATP竞争性类似物1 NM-PP 1特异性抑制“类似物敏感”突变体AS-Jak 1而非AS-Jak 3可消除IL-2信号传导，证实了选择性Jak 3抑制剂的数据。因此，Jak 1在Jak 3上起着主导作用，这些数据挑战了选择性ATP竞争性Jak 3激酶抑制剂有效的概念。
Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain (gamma c) and thus to immunodeficiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. Jak1 cooperates with Jak3 in signaling through gamma c-containing receptors. Unexpectedly, a Jak3-selective inhibitor was less efficient in abolishing STAT5 phosphorylation than pan-Jak inhibitors. We therefore explored the roles of Jak1 and Jak3 kinase functionality in signaling using a reconstituted system. The presence of kinase-inactive Jak1 but not kinase-inactive Jak3 resulted in complete abolishment of STAT5 phosphorylation. Specific inhibition of the "analog-sensitive" mutant AS-Jak1 but not AS-Jak3 by the ATP-competitive analog 1NM-PP1 abrogated IL-2 signaling, corroborating the data with the selective Jak3 inhibitor. Jak1 thus plays a dominant role over Jak3 and these data challenge the notion that selective ATP-competitive Jak3 kinase inhibitors will be effective.