NORMAL AND ABNORMAL INTERFERON ALPHA RECEPTORS

干扰素（IFN）、细胞因子和生长因子在肿瘤的发生发展中起重要作用， 第一道防线对抗病毒感染，在治疗不同的 癌症类型和免疫和造血调节 系统 它们的影响几乎涉及生物体的每个系统 强调其广泛影响以及阐明其 信号机制。 细胞因子、生长因子和干扰素具有类似的 涉及受体结合和激活的信号传导机制 酪氨酸激酶和转录因子的Jak和Stat（信号 转导子和转录激活子）家族，这导致 基因的转录激活负责不同的 细胞因子反应。 然而，关于细胞因子在细胞内表达的机制知之甚少。 受体激活Jak激酶和Stat因子。 本申请 试图描述细胞因子受体的机制， 激活Jak激酶 我们将检验类似的假设， 存在于细胞因子受体的胞质区域中的结构域可以是 用于Jak激酶的相互作用和激活。 但是，在这方面， 这种胞质结构域在激活 Jak 1和Jak 2通过不同的受体。 在第一个具体目标中， 一项提案的重点是Jak 1结合结构域的表征 存在于激活这种激酶的不同细胞因子受体中。 我们 还将描述Jak激酶中的结构域， 与不同细胞因子受体的相互作用。 第二 提出的具体目标是测试相互作用的不同模型/ 细胞因子受体和Jak激酶之间的激活，强调了 细胞因子受体与Jak 1和Jak 2的相互作用/活化。 为了实现这些目标，我们提出了体内和体外研究，如 产生GST融合蛋白编码突变的 合适的结合位点，双杂交系统，重组蛋白的制备 使用体外翻译系统的蛋白质，瞬时和稳定 重组蛋白在不同哺乳动物细胞中的表达。 的 这一建议所取得的成果不仅对 了解IFN α的信号通路，但也通过 不同的细胞因子受体。

Interferons (IFN), cytokines and growth factors play important roles as a first defense against viral infections, in the treatment of different types of cancers and in the regulation of the immune and hematopoietic system. Their effects involve almost every system in the organism underscoring their broad effects and the importance of elucidating their signaling mechanisms. Cytokine, growth factors and IFNs have similar signaling mechanism that involve receptor binding and activation of tyrosine kinases and transcription factors of the Jak and Stat (Signal Transducers and Activators of Transcription) families, that results in the transcriptional activation of genes responsible for the different cytokine responses. However, little is known about the mechanisms by which cytokine receptors activate the Jak kinases and Stat factors. This application attempts to characterize the mechanisms used by cytokine receptors to activate the Jak kinases. We will test the hypothesis that similar domains present in the cytoplasmic region of cytokine receptors may be utilized for the interaction and activation of Jak kinases. However, this cytoplasmic domain may have different roles in the activation of Jak1 and Jak2 by distinct receptors. In the first Specific Aims of this proposal is focused on the characterization of the Jak1 binding domain present in different cytokine receptors that activate this kinase. We will also characterize the domains in the Jak kinases that are required for the interaction with different cytokine receptors. The second Specific Aim proposed to test different models for the interaction/ activation between cytokine receptors and Jak kinases, stressing the interaction/activation of cytokine receptors with Jak1 and Jak2. To achieve these goals we propose in vivo and in vitro studies such as the production of GST fusion protein encoding mutation of the appropriate binding sites, two hybrid system, production of recombinant proteins using in vitro translation systems, transient and stable expression of recombinant proteins in different mammalian cells. The results obtained with this proposal will be important not only to understand the signaling pathway of IFNalpha, but also signaling by different cytokine receptors.