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

多种细胞因子利用Janus kinase （JAK）和转录信号转导及激活因子（STAT）家族来发挥其生物学功能。酪氨酸磷酸化的STATs形成同源或异源二聚体并转运到细胞核中，然后激活靶基因。与其他激酶相比，我们对jak的细胞调节因子知之甚少。CIS（细胞因子-不可清除SH2蛋白）蛋白家族最近被发现与多种细胞因子的信号转导有关，CIS1是该家族的第一个成员，作为一个直接早期基因被克隆，可响应多种细胞因子，包括促红细胞生成素（EPO）、白细胞介素2 （1L2）、1L3和GM-CSF，并由STAT5调节。CIS1结合酪氨酸磷酸化的il - 3和EPO受体，并负调控STAT5。第二个家族成员被三个小组独立克隆，称为JAB、SOCS-1或SSI-1（6,20,29）。IFNgam可诱导JAB，抑制lFN和IL6信号。JAB和CIS直接结合到JAKs的激酶结构域，从而抑制激酶活性。通过与Ihie博士的团队合作，我们已经培育出了JAB和CIS3基因敲除小鼠，现在我们正在对它们进行分析。我们证明JAB特异性结合JAK2激活环中的酪氨酸残基（Y1007），其磷酸化是激活激酶活性所必需的。JAB的另一个n端12个氨基酸区（激酶抑制区）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必需的。我们的研究定义了一种新的酪氨酸激酶调控类型，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的激活尚不清楚。我们报道了CIS1结合到含有第二酪氨酸残基（Y401）的EPO受体区域。其中一种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-蛋白酶途径加速了受体-CIS1复合物的降解。CIS1抑制STAT5的机制有待进一步研究。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