Physiological Function and Signal Transduction Mechanism of the STAT5-target genes

多种细胞因子利用Janus激酶（JAK）和信号转导和转录激活因子（STAT）家族的转录因子发挥其生物学功能。酪氨酸磷酸化的STAT形成同源或异源二聚体并易位到细胞核中，然后激活靶基因。与其他激酶相比，JAK的细胞调节因子知之甚少。CIS（casein-indelible SH 2 protein）家族是近年来发现的一个与多种细胞因子信号转导有关的蛋白质家族。CIS 1是该家族的第一个成员，是一个对多种细胞因子（包括促红细胞生成素（EPO）、白细胞介素2（IL 2）、IL 3和GM-CSF）产生应答的立即早期基因，受STAT5的调节。CIS 1与酪氨酸磷酸化的IL 3和EPO受体结合，并负调节STAT 5。第二个家族成员由三个组独立克隆，并被称为JAB、SOCS-1或SSI-1（6，20，29）。JAB由IFN γ诱导 ...更多信息 ma并抑制IFN以及IL 6信号传导。JAB和CIS直接与JAK的激酶结构域结合，从而抑制激酶活性。通过与Ihie博士的团队合作，我们已经创建了JAB和CIS 3基因敲除小鼠，我们现在正在分析它们。我们证明，JAB特异性结合的酪氨酸残基（Y1007）在激活环的JAK2的磷酸化是必需的激酶活性的激活。JAB的另外的N-末端12个氨基酸区域（激酶抑制区域）也有助于与JAK2酪氨酸激酶结构域的高亲和力结合，并且是抑制JAK2信号传导和激酶活性所需的。我们的研究定义了一种新型的酪氨酸激酶调节，并可能为设计特异性酪氨酸激酶抑制剂提供基础。另一方面，CIS1如何抑制STAT5激活尚不清楚。我们报道了CIS1与EPO受体的第二个酪氨酸残基（Y401）结合。其中一个机制是简单地掩盖受体上的STAT5结合位点。另一种可能性是CIS1通过泛素-蛋白酶途径加速受体-CIS1复合物的降解。需要进一步研究以阐明CIS1抑制STAT5的机制。少

A variety of cytokines utilizes Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) family of transcription factors, to exert their biological functions. The tyrosinephosphorylated STATs form homo- or heterodimers and translocate into the nucleus, then activate target genes. Compared with other kinases, little is known about cellular regulators of the JAKs. The CIS (cytokine-indelible SH2 protein) family of proteins that w found recently has been implicated in regulating signal transduction by a variety of cytokines, The first member of this family, CIS1 was cloned as an immediate early gene responding to a number of cytokines including erythropoietin (EPO), interleukin 2 (1L2), 1L3 and GM-CSF, and is regulated by STAT5. CIS1 binds to the tyrosine phosphorylated IL3 and EPO receptors, and negatively regulates STAT5, The second family member was independently cloned by three groups and is termed JAB, SOCS-1, or SSI-1 (6, 20, 29). JAB is induced by IFNgam … More ma and inhibits lFN as wellas IL6 signaling. JAB and CIS directly bind to the kinase domain of JAKs, thereby inhibiting the kinase activity. In collaboration with Dr. Ihie's group, we already created JAB and CIS3 genes knockout mice and we are analyzing them now. 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. An additional N-terminal 12 amino acid region (kinase inhibitory region) of JAB also contributes to high affinity binding to the JAK2 tyrosine kinase domain and is required for inhibition of JAK2 signaling and kinase activity. Our studies define a novel type of regulation of tyrosine kinases and might provide a basis for the design of specific tyrosine kinase inhibitors, On the other hand, it has not been clear how CIS1 suppresses STAT5 activation. We reported that CIS1 binds to the region of the EPO receptor containing the second tyrosine residue (Y401). One of the mechanisms is simply masking the STAT5 binding sites on the receptor. The other possibility is that CIS1 accelerates degradation of the receptor-CIS1 complex by the ubiquitin-proteaspme pathway. Further study is necessary to elucidate the mechanism of STAT5 inhibition by CIS1. Less