Stat3在多种恶性肿瘤中的作用

Stat3是转录信号转导子与激活子家族（Stats）的重要成员,广泛表达于不同类型的细胞和组织中,受大量细胞因子、生长因子和癌基因调节,其生物学功能广泛,在调节细胞增殖、存活和分化方面起着关键作用。持续激活的Stat3（p-Stat3）在许多恶性肿瘤中已经发现,包括人类白血病、头颈部鳞状细胞癌、乳腺癌、前列腺癌、肺癌、胰腺癌和黑色素瘤等,p-Stat3与恶性肿瘤的发生、发展及转移密切相关。因此,Stat3已成为近年来肿瘤治疗研究探讨的新靶点,以Stat3为靶点的分子治疗有可能为肿瘤治疗翻开新的一页。     

Janus kinases in immune cell signaling

Summary:  The Janus family kinases (Jaks), Jak1, Jak2, Jak3, and Tyk2, form one subgroup of the non-receptor protein tyrosine kinases. They are involved in cell growth, survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. Data from experimental mice and clinical observations have unraveled multiple signaling events mediated by Jaks in innate and adaptive immunity. Deficiency of Jak3 or Tyk2 results in defined clinical disorders, which are also evident in mouse models. A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome. By contrast, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and, unsurprisingly, do not have counterparts in human disease. However, activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Our existing knowledge on Jak signaling pathways and fundamental work on their biochemical structure and intracellular interactions allow us to develop new strategies for controlling autoimmune diseases or malignancies by developing selective Jak inhibitors, which are now coming into clinical use. Despite the fact that Jaks were discovered only a little more than a decade ago, at the time of writing there are 20 clinical trials underway testing the safety and efficacy of Jak inhibitors.     

The Jak-STAT pathway

A variety of important cellular functions are regulated by cytokines. The Jak-STAT pathway is one of the important signaling pathways downstream of cytokine receptors. Following binding of a ligand to its cognate receptor, receptor-associated Jaks are activated. STAT proteins are then in turn activated by tyrosine phosphorylation by Jak kinases, allowing their dimerization and subsequent translocation into the nucleus, where they modulate expression of target genes. Indispensable functions of Jaks and STATs in cytokine signaling in vivo have been revealed through knockout mouse studies. Moreover, the recent discovery of the CIS/SOCS/JAB/SSI family of inhibitors has contributed to understanding how this pathway is negatively regulated.     

受体相互作用蛋白激酶RIP1在细胞信号转导途径中作用的研究进展

 受体相互作用蛋白1是一类丝氨酸/苏氨酸蛋白激酶,是一种重要的细胞信号转导分子,从其被发现开始就成为了细胞信号转导的研究热点,但多集中在其在细胞凋亡中的作用,近年来的研究表明,受体相互作用蛋白1不仅参与了细胞的凋亡,还参与了细胞存活,细胞程序性坏死等多种信号的转导,是一类重要的调节细胞生存或死亡的信号分子,本文对受体相互作用蛋白1功能的研究进展做简要综述。     

IL-13 signal transduction in human monocytes: phosphorylation of receptor components,association with Jaks,and phosphorylation/activation of Stats

Interleukin (IL)-13 regulates monocyte function and is a potent stimulator of 15-lipoxygenase expression. In different cell types, the functional IL-13 receptor complex can be comprised of variable protein components and has not been thoroughly examined in human monocytes. Here, we identify the receptor components and upstream signaling events initiated by IL-13 in primary human blood monocytes. The expression, phosphorylation and associated Jak kinases of the known, variable receptor components, IL-4R(alpha), IL-2Rgammac, IL-13R(alpha)1 and IL-13R(alpha)2, were examined. We determined that IL-4R(alpha) and IL13R(alpha)1 are phosphorylated upon exposure to IL-13. Although IL-2Rgammac is also expressed, it is not phosphorylated upon exposure to IL-13. Evaluation of the presence of IL-13R(alpha)2 failed to reveal significant mRNA or protein expression. Earlier, our laboratory showed that IL-13 induced the phosphorylation of Jak2 and Tyk2 in monocytes and that expression of both Jaks was essential for downstream signaling by IL-13. Here, we report that Jak2 is associated with IL-4R(alpha), and Tyk2 is associated with the IL-13R(alpha)1 component of the IL-13 receptor complex. Additionally, Stat proteins 1alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. Further, the nuclear translocation and DNA binding of each of these Stats were induced by IL-13. These data represent the first complete report of the functional IL-13 receptor complex and early signaling events in human monocytes. This information is critical for understanding the IL-13 response of monocytes in inflammation.