Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
PLoS One. 2012;7(6):e39141. doi: 10.1371/journal.pone.0039141. Epub 2012 Jun 18.
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2(K923E)) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein's stability. An inhibitory function was only observed upon over-expression of TYK2(K923E)in vitro. Tyk2(K923E) mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors.
酪氨酸激酶 2（TYK2）是 Janus 激酶（JAK）家族的一员，参与细胞因子信号转导。体外分析表明，TYK2 还具有激酶非依赖性的，即非经典的，功能。我们已经生成了携带激酶结构域 ATP 结合口袋突变的基因靶向小鼠。TYK2 激酶失活（Tyk2（K923E））小鼠是可行的，没有明显的异常。我们表明，激酶活性 TYK2 是完全 I 型干扰素（IFN）诱导的转录因子 STAT1-4 的激活所必需的，并且是体内抗病毒防御的必需的，主要通过 I 型 IFN 作用来控制。此外，发现 TYK2 激酶活性是蛋白质稳定性所必需的。仅在体外过度表达 TYK2（K923E）时才观察到抑制功能。Tyk2（K923E）小鼠代表了研究体内 JAK 激酶非依赖性功能和评估 JAK 抑制剂副作用后果的首个模型。
