Analysis of cyto kine signal transduction

Janus激酶(JAKs)通过与细胞因子受体结合，调节细胞生长、分化和转化过程。最近，JAK结合蛋白(JAB)被鉴定为JAK抑制因子。我们证明Jab与JAK2激活环中的酪氨酸残基(Y1007)特异性结合，该残基的磷酸化是激活激酶活性所必需的。Tyk2是一种Janus激酶，我们建立了TYK2缺陷小鼠来研究体内对TYK2的需求。TYK2基因缺陷小鼠没有表现出明显的发育异常，但它们对少量干扰素γ缺乏反应性，尽管即使在没有TYK2的情况下，高浓度的干扰素γ也可以完全传递其信号。此外，IL-12诱导的T细胞功能在这些小鼠中是有缺陷的。相比之下，这些小鼠对IL-6和IL-10的反应正常，这两种物质都在体外激活了TYK2。这些观察结果表明，TYK2只在介导干扰素γ依赖的信号转导中发挥有限的作用，而在介导IL-12依赖的生物反应中却是必需的。STAT家族的一个成员是STAT3，它主要由IL-6家族的细胞因子、表皮生长因子和瘦素激活。像STAT家族的其他成员一样，STAT3被Jak激酶酪氨酸磷酸化，在此基础上它二聚体，并移位到细胞核中激活目标基因。我们提供的证据表明，雌激素受体对STAT3活性的抑制作用是由于STAT3和雌激素受体之间的直接物理相互作用，这代表了STAT3和ER信号通路之间的一种新的串扰形式。

Janus kinases (Jaks) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. Recently, Jak-binding protein (JAB) was identified as a JAK inhibitor. We demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity.Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities, however they display a lack of responsiveness to a small amount of IFNγ, although a high concentration of IFNγ can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNγ-dependent signaling, whilst being required in mediating IL-12-dependent biological responses.One member of the STAT family of proteins is STAT3, which is mainly activated by IL-6 family of cytokines, epidermal growth factor, and leptin. Like other members of the STAT family, STAT3 is tyrosine-phosphorylated by Jak kinases, upon which it dimerizes, and translocates into the nucleus to activate target genes. We provided evidence that the inhibitory action of estrogen receptor on STAT3 activity was due to direct physical interactions between STAT3 and estrogen receptor, which represents a novel form of cross-talk between STAT3 and ER signaling pathways.