TWEAK signaling pathway

TNF related weak inducer of apoptosis (TWEAK) is a small pleiotropic cytokine of the TNF super family and its gene is located at chromosome 17p13.1. TWEAK has been reported to be expressed in tissues that include heart, brain, kidney and also in mononuclear blood cells. The multiple biological activities of TWEAK include stimulation of cell growth and angiogenesis, induction of inflammatory cytokines, and stimulation of apoptosis. It has been shown to be involved in the induction of cellular proliferation in liver cells, osteoblasts, astrocytes, synoviocytes, kidney cells and skeletal muscles. Furthermore, TWEAK plays a substantial role in cellular differentiation in osteoclasts. TWEAK induces glioma cell survival via imparting resistance to cytotoxic agents. It imparts its downstream signaling events by binding to its receptor, FGF inducible 14 protein (Fn14). Two modes of TWEAK-Fn14 (ligand-receptor) interactions have been proposed (i) the ligand dependent interaction which involves the higher concentration of homotrimeric TWEAK, that binds to low concentration of Fn14 in a heterohexameric complex (ii) ligand-independent interaction when the ligand concentration is lower than the receptor concentration which induces the ligand independent interaction. The receptors homotrimerize to activate the downstream events. The signaling cascades reported under TWEAK-Fn14 interactions are the canonical and noncanonical NF-κB pathways and the MAPK pathway. There has been a report on crosstalk between Wnt and TWEAK pathways. In myoblasts the PI3K-AKT module has been reported to be inhibited under TWEAK stimulus. AKT phosprorylation leads to the activation of GSK3β resulting in increase of phospho-GSk3β and active β-catenin1 (CTNNB1) (dephosphorylated) levels. GSK3β and β-catenin1 remain associated in the cytoplasm, phosphorylation of GSK3β leads to the dissociation of β-catenin1 (dephosphorylated) resulting in the nuclear translocation of the protein. Despite of reports on TWEAK binding to other receptors including CD163 and DR3 the downstream events following the binding is yet to be established. The data provided by us would foster enormous avenues for further studies on TWEAK associated proteins and the related disorders such as cancer and autoimmune diseases. The data would enable therapeutic studies by selecting the pathological events and the simultaneous production of blocking agents. Despite the minimal amount of data, ours can also be used in the overlay of various high throughput data enabling pathway analysis and can be accessed by any pathway resource to generate a customized pathway. Please access this pathway at [http://www.netpath.org/netslim/tweak_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Bhattacharjee, M., Raju, R., Radhakrishnan, A., Nanjappa, V., Muthusamy, B., Singh, K., Kuppusaami, D., Lingala, B. T., Pan, A., Mathur, P. P., Harsha, H. C., Prasad, T. S. K., Atkins, G. J., Pandey, A. and Chatterjee, A. (2012). A Bioinformatics Resource for TWEAK-Fn14 Signaling Pathway. Journal of Signal Transduction. In press.

TNF相关弱凋亡诱导因子（TWEAK）是一种小型的多效性细胞因子，属于TNF超家族，其基因定位于17p13.1染色体上。TWEAK在包括心脏、大脑、肾脏以及单核血细胞在内的多种组织中均有表达。TWEAK的多重生物学活性包括促进细胞生长和血管生成、诱导炎症细胞因子以及促进细胞凋亡。研究表明，TWEAK参与肝细胞、成骨细胞、星形胶质细胞、滑膜细胞、肾脏细胞和骨骼肌中细胞增殖的诱导。此外，TWEAK在破骨细胞分化过程中亦发挥着重要作用。TWEAK通过赋予细胞对细胞毒性药物的抵抗性，从而诱导胶质瘤细胞的存活。它通过与其受体FGF诱导的14蛋白（Fn14）结合，传递其下游信号事件。已提出的TWEAK-Fn14（配体-受体）相互作用模式有两种：（i）配体依赖性相互作用，涉及高浓度的同源三聚体TWEAK，与低浓度的Fn14在异源六聚体复合物中结合；（ii）配体非依赖性相互作用，当配体浓度低于受体浓度时引发。受体同源三聚化以激活下游事件。报道的TWEAK-Fn14相互作用中的信号级联包括经典和非经典NF-κB途径以及MAPK途径。已有Wnt和TWEAK途径之间的串扰报道。在肌细胞中，PI3K-AKT模块在TWEAK刺激下已被报道受到抑制。AKT磷酸化导致GSK3β的激活，进而引起磷酸化GSK3β和活性β-catenin1（CTNNB1）（去磷酸化）水平的增加。GSK3β和β-catenin1在细胞质中保持关联，GSK3β的磷酸化导致β-catenin1（去磷酸化）的解离，从而引起蛋白质的核转位。尽管有TWEAK与CD163和DR3等其他受体结合的报告，但其结合后的下游事件尚未得到确立。我们提供的数据将为TWEAK相关蛋白及其相关疾病，如癌症和自身免疫性疾病的研究开辟广阔的途径。这些数据将使治疗研究得以进行，通过选择病理事件和同步生产阻断剂。尽管数据量有限，我们的数据也可用于各种高通量数据的叠加，以实现通路分析，并可被任何通路资源用于生成定制通路。请访问[http://www.netpath.org/netslim/tweak_pathway.html NetSlim]数据库。如果使用此通路，请引用以下论文：Bhattacharjee, M.，Raju, R.，Radhakrishnan, A.，Nanjappa, V.，Muthusamy, B.，Singh, K.，Kuppusaami, D.，Lingala, B. T.，Pan, A.，Mathur, P. P.，Harsha, H. C.，Prasad, T. S. K.，Atkins, G. J.，Pandey, A. 和 Chatterjee, A. (2012). TWEAK-Fn14信号通路生物信息学资源。信号转导杂志。即将出版。