IL-7 signaling pathway

Interleukin-7 (IL-7) was discovered in the year 1988 as a factor that enhanced the growth of murine B-cell precursors in bone marrow culture system. It was also known as lymphopoietin 1and pre-B cell factor. IL-7 plays an important role in the development of B and T cells in mouse and T cells in humans. It is also essential for mature and naive T-cell's survival and proliferation. Human IL-7 gene maps to chromosome 8 and is about 72kb in length. The protein encoded by this gene is 177 amino acids in length with a molecular weight of 20 kDa. The active form of IL-7 in humans is a glycoprotein of 25 kDa. In humans IL-7 has been shown to be produced from intestinal epithelial cells, keratinocytes , hepatic tissues, peripheral blood dendritic cells, follicular dendritic cells, endothelial cells, smooth muscle cells and fibroblasts. The IL-7 receptor consists of IL-7 receptor alpha chain (IL-7Rα) and a common gamma chain (γc). The gamma chain is also shared by IL-2, IL-4, IL-9, IL-15 and IL-21 receptors. The signaling pathways activated upon IL-7 binding to the receptor complex are JAK-STAT, PI-3 kinase and Src kinase pathways. JAK3, a protein tyrosine kinase is constitutively associated with the carboxy-terminal region of the gamma chain. Studies in mice lacking JAK3 have shown that it is required for transducing γc dependent signals. Mutations in JAK3 and γc have been shown to be associated with the autosomal recessive form of T-B + SCID. JAK1, another protein tyrosine kinase is associated with IL-7Rα chain and is activated upon IL-7 binding. JAK1 deficient mice shows severely impaired thymic development and no hematopoietic colony formation in response to IL-7. IL-7 would first bind to IL-7Rα and then associates with the gamma chain, bringing their intracellular domains bearing JAK1 and JAK3 together. JAK3 phosphorylates IL-7Rα chain creating docking sites for the transcription factors, STAT1, STAT3, and STAT5. JAK1 and JAK3 phosphorylate these STAT molecules and induces their dimerization and translocation to the nucleus where they activate specific target genes. PTK2B, a protein tyrosine kinase has been shown to be associated with JAK1 and plays an important role in the survival of thymocyte cell line. The enzymatic activity and its phosphorylation are highly induced by IL-7. PI-3 kinase pathway is also activated by IL-7 and this pathway is essential for the survival and proliferation of human T cell precursors. PI-3 kinase interacts with IL-7Rα upon IL-7 stimulation and activates its downstream target, AKT and its activation is mediated by γc. AKT in turn activates GSK3 beta and Bad, the death protein. Survival of pro T-cell survival by regulating Bad via PI3 kinase/AKT pathway is mediated by IL-7. IL-7 also mediates the downregulation of cyclin-dependent kinase inhibitor 1B through the PI-3 kinase pathway and this effect is required for cell proliferation. IL-7 also induces the phosphorylation of a Src kinase family member, Fyn which is constitutively associated with IL7RA. In addition, IL-7 induces phosphorylation of MAPK family members including MAPK1 and MAPK3. Please access this pathway at [http://www.netpath.org/netslim/IL_7_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. <i>Genome Biology</i>. 11:R3.

白细胞介素-7（IL-7）于1988年被发现，作为一种促进骨髓培养系统中小鼠B细胞前体细胞生长的因子。它也被称为淋巴生成素1和前B细胞因子。IL-7在B和T细胞的发育中发挥着重要作用，尤其是在小鼠的B细胞和人类的T细胞中。它对成熟和原始T细胞的存活和增殖也至关重要。人类IL-7基因定位于第8号染色体，长度约为72kb。该基因编码的蛋白质由177个氨基酸组成，分子量为20 kDa。人类IL-7的活性形式是一种分子量为25 kDa的糖蛋白。在人类中，IL-7已被证明由肠道上皮细胞、角质细胞、肝组织、外周血树突状细胞、滤泡树突状细胞、内皮细胞、平滑肌细胞和成纤维细胞产生。IL-7受体由IL-7受体α链（IL-7Rα）和共同的γ链（γc）组成。γ链也与其他IL-2、IL-4、IL-9、IL-15和IL-21受体共享。IL-7与受体复合物结合后激活的信号通路包括JAK-STAT、PI-3激酶和Src激酶通路。JAK3，一种蛋白酪氨酸激酶，与γ链的羧基末端区域构成性结合。在缺乏JAK3的小鼠研究中显示，JAK3对于传递γc依赖性信号是必需的。JAK3和γc的突变已被证明与常染色体隐性形式的T-B+SCID相关。JAK1，另一种蛋白酪氨酸激酶，与IL-7Rα链相关，并在IL-7结合时被激活。JAK1缺陷小鼠显示出严重的胸腺发育受损，以及对IL-7无造血集落形成。IL-7首先与IL-7Rα结合，然后与γ链结合，将带有JAK1和JAK3的细胞内结构域聚集在一起。JAK3磷酸化IL-7Rα链，为转录因子STAT1、STAT3和STAT5提供对接位点。JAK1和JAK3磷酸化这些STAT分子，诱导其二聚化并转移到细胞核，在那里它们激活特定的靶基因。PTK2B，一种蛋白酪氨酸激酶，已被证明与JAK1相关，并在胸腺细胞系存活中发挥重要作用。IL-7高度诱导其酶活性及其磷酸化。PI-3激酶通路也被IL-7激活，该通路对于人类T细胞前体的存活和增殖至关重要。PI-3激酶在IL-7刺激下与IL-7Rα相互作用，并激活其下游靶点AKT，其激活由γc介导。AKT反过来又激活GSK3 beta和Bad，即死亡蛋白。通过PI3激酶/AKT通路调节Bad的存活，是IL-7介导的。IL-7还通过PI-3激酶通路下调细胞周期依赖性激酶抑制因子1B，这一效应对于细胞增殖是必需的。IL-7还诱导Src激酶家族成员Fyn的磷酸化，Fyn与IL7RA构成性结合。此外，IL-7诱导MAPK家族成员，包括MAPK1和MAPK3的磷酸化。请访问[http://www.netpath.org/netslim/IL_7_pathway.html NetSlim]数据库。如使用此通路，请引用以下论文：Kandasamy, K.，Mohan, S. S.，Raju, R.，Keerthikumar, S.，Kumar, G. S. S.，Venugopal, A. K.，等（2010）. NetPath: 一个公共的信号转导通路资源。《基因组生物学》。11：R3。