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

多种细胞因子利用Janus激酶(JAK)和信号转导及转录激活因子(STAT)家族转录因子发挥其生物学功能。酪氨酸磷酸化的STATs形成同源或异源二聚体，并移位到细胞核中，然后激活目标基因。与其他激酶相比，JAK的细胞调控机制知之甚少。最近发现的细胞因子不可磨灭SH2蛋白家族参与了多种细胞因子对信号转导的调控，该家族中的第一个成员CIS1被克隆为对包括促红细胞生成素(EPO)、白介素2(IL-2)、1L3和GM-CSF在内的多种细胞因子的即刻早期基因，并受STAT5调控。Cis1结合酪氨酸磷酸化的IL3和EPO受体，负调控STAT5，第二个家族成员由三个小组独立克隆，命名为Jab，SoCS-1，或SSI-1(6，20，29)。JAB由IFNgam…诱导更多的MA和抑制LFN和IL6信号。Jab和CIS直接与JAKs的激酶结构域结合，从而抑制该激酶的活性。在与Ihie博士的团队的合作下，我们已经创造了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。JAB的一个额外的N-末端12个氨基酸区域(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，这是抑制JAK2信号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的调节类型，并可能为设计特定的酪氨酸激酶抑制剂提供基础，另一方面，还不清楚CIS1是如何抑制STAT5的激活的。我们报道了CIS1与EPO受体包含第二个酪氨酸残基的区域(Y401)结合。其中一个机制是简单地屏蔽受体上的STAT5结合位点。另一种可能是Cis1通过泛素-蛋白天冬氨酸蛋白酶途径加速受体-Cis1复合体的降解。需要进一步的研究来阐明Cis1抑制STAT5的机制。较少

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