REGULATION OF TNF RECEPTOR SIGNALING AND FUNCTIONS

描述（改编自申请人的摘要）：TNF α受体 CD 120 a或p55在急性和慢性肿瘤的发展中起着关键作用。 炎症性疾病的肺部通过其信号的能力，启动 包括促炎细胞因子的产生和细胞 生存和死亡研究者已经表明，CD 120 a被磷酸化， ERK。一旦磷酸化，质膜上的受体表达 微区（称为受体筏）丢失，受体变成 与内质网（ER-丝）的元件相关。作为 磷酸化的结果，细胞变得对磷酸化的诱导具有抗性。 凋亡性细胞死亡仍保留激活转录的能力， NF-κ B因子。这可能会导致细胞的保存过程中， 炎症反应在肺和肺癌，并可能导致 延长促炎基因表达。本提案的总体目标是 是研究肿瘤坏死因子受体的地形分布是如何 调节，以及这种分布如何调节受体的模式 发信号。假设：1）磷酸化诱导了运输 CD 120 a（p55）从受体筏到ER-丝的作用 新的CD 120 a（p55）相互作用蛋白，TRIP 197和pTRIP 82;和2） 将磷酸化受体定位于ER-丝可防止细胞凋亡 通过在ER组装促存活信号复合物导致细胞死亡 膜的这些假设将通过三个具体目标来解决：1） 确定去磷酸化的CD 120 a（p55）如何定位于受体筏， TRIP 197的特异性作用; 2）研究TRIP 197的易位机制， 磷酸化的CD 120 a（p55）转化为ER-丝以及pTRIP 82在此过程中的作用 事件;和3）研究细胞被保护免受 CD 120 a（p55）磷酸化后的细胞凋亡。这项工作的成果将有 理解CD 120 a（p55）的地形信号传导是如何 在炎症性疾病和肺癌中受到调节。

DESCRIPTION (Adapted from the Applicant's Abstract): The TNFalpha receptor CD120a, or p55, plays a critical role in the development of acute and chronic inflammatory diseases of the lung through its ability to signal the initiation of functions that include pro-inflammatory cytokine production and cell survival and death. The investigator has shown that CD120a is phosphorylated by the ERK. Once phosphorylated, receptor expression in plasma membrane microdomains (referred to as receptor rafts) is lost, and the receptor becomes associated with elements of the endoplasmic reticulum (ER-filaments). As a consequence of phosphorylation, cells become resistant to the induction of apoptotic cell death yet retain the ability to activate the transcription factor NF-kB. This may lead to the preservation of cells during the inflammatory response in the lung and in lung cancer, and may result in prolonged pro-inflammatory gene expression. The overall goal of this proposal is to investigate how the topographic distribution of the TNF receptor is regulated, and how this distribution regulates the pattern of receptor signaling. It is hypothesized: 1) that phosphorylation induces the trafficking of CD120a (p55) from receptor rafts to ER-filaments through the actions two novel CD120a (p55)-interacting proteins, TRIP197 and pTRIP82; and 2) that localization of the phosphorylated receptor to ER-filaments prevents apoptotic cell death by the assembly of a pro-survival signaling complex at the ER membrane. These hypotheses will be addressed by three specific aims: 1) to determine how de-phosphorylated CD120a (p55) is localized to receptor rafts and the specific role of TRIP197; 2) investigate the mechanism of translocation of phosphorylated CD120a (p55) to ER-filaments and the role of pTRIP82 in this event; and 3) investigate the mechanism by which cells are protected from apoptosis upon CD120a (p55) phosphorylation. The outcome of this work will have implications for understanding how topographical signaling by CD120a (p55) is regulated in inflammatory diseases and cancers of the lung.