Usacheva A, Smith R, Minshall R, Baida G, Seng S, Croze E, Colamonici O
Department of Pharmacology, University of Illinois, Chicago, Illinois 60612, USA.
J Biol Chem. 2001 Jun 22;276(25):22948-53. doi: 10.1074/jbc.M100087200. Epub 2001 Apr 11.
An obligatory step in the activation of Signal Transducers and Activators of Transcription (STATs) by cytokines is their docking to specific receptors via phosphotyrosines. However, this model does not address whether STATs pre-associate with their corresponding receptor or exist free in the cytoplasm before receptor activation. In this report, we demonstrate that pre-association of STAT1 with the receptor is required for type I interferon (IFN) signaling. Interestingly, the interaction between the human type I IFN receptor and STAT1 is not direct but mediated by the adapter protein receptor for activated protein kinase C (RACK1). Disruption of the IFNalpha receptor-RACK1 interaction abolishes not only IFNalpha-induced tyrosine phosphorylation of STAT1 but also activation of STAT2, indicating that RACK1 plays a central role in early signaling through the Jak-STAT pathway. These findings demonstrate the involvement of RACK1 in STAT1 activation and raise the possibility that other STATs may pre-associate with cytokine receptors through similar adapter-STAT-mediated interactions.
细胞因子激活信号转导和转录激活因子（STATs）的一个必要步骤是它们通过磷酸酪氨酸与特定受体对接。然而，该模型并未解决STATs是否在受体激活之前就与相应受体预先结合或在细胞质中游离存在的问题。在本报告中，我们证明STAT1与受体的预先结合是I型干扰素（IFN）信号传导所必需的。有趣的是，人类I型干扰素受体与STAT1之间的相互作用不是直接的，而是由衔接蛋白活化蛋白激酶C受体（RACK1）介导的。干扰素α受体与RACK1相互作用的破坏不仅消除了干扰素α诱导的STAT1酪氨酸磷酸化，也消除了STAT2的激活，表明RACK1在通过Jak-STAT途径的早期信号传导中起核心作用。这些发现证明了RACK1参与STAT1的激活，并增加了其他STATs可能通过类似的衔接蛋白-STAT介导的相互作用与细胞因子受体预先结合的可能性。
