Yan H, Krishnan K, Greenlund A C, Gupta S, Lim J T, Schreiber R D, Schindler C W, Krolewski J J
Department of Pathology, Columbia-Presbyterian Cancer Center, Columbia University, New York, NY 10032, USA.
EMBO J. 1996 Mar 1;15(5):1064-74.
Interferon-alpha (IFN alpha) induces rapid tyrosine phosphorylation of its receptors, two JAK kinases and three STAT transcription factors. One kinase, p135tyk2, is complexed with the IFNaR1 receptor, and may catalyze some of these phosphorylation events. We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2. These observations are consistent with a model in which IFNaR1 mediates the interaction between JAK kinases and the STAT transcription factors.
α干扰素（IFNα）可诱导其受体、两种JAK激酶和三种STAT转录因子迅速发生酪氨酸磷酸化。一种激酶p135tyk2与IFNaR1受体形成复合物，并可能催化其中一些磷酸化事件。我们证明，在体外，p135tyk2可使IFNaR1上的两个酪氨酸发生磷酸化。对应于主要磷酸化位点（Tyr466）的磷酸肽以SH-2依赖的方式结合STAT2，但不结合STAT1。此外，只有潜在的、未磷酸化的STAT2与该磷酸肽相互作用。当将该磷酸肽导入通透细胞时，两种STAT的IFNα依赖性酪氨酸磷酸化均被阻断。最后，将Tyr466突变为苯丙氨酸的IFNaR1突变体可呈显性负性作用，抑制STAT2的磷酸化。这些观察结果与IFNaR1介导JAK激酶与STAT转录因子之间相互作用的模型一致。
