REGULATION OF TNF RECEPTOR SIGNALING AND FUNCTIONS

描述(摘自申请者摘要)：肿瘤坏死因子α受体 CD120a或p55在急性和慢性白血病的发生发展中起关键作用。 肺炎性疾病通过其发出信号的能力启动 包括促炎细胞因子的产生和细胞 生存与死亡。研究人员已经证明，CD120a是由 ERK。一旦被磷酸化，受体在质膜上的表达 微域(称为受体筏)丢失，受体变成 与内质网元素(内质网细丝)有关。作为一名 磷酸化的后果，细胞变得对诱导 细胞凋亡性死亡仍能激活转录 核因子-kB。这可能会导致细胞在 肺部和肺癌中的炎症反应，并可能导致 长时间的促炎基因表达。这项提案的总体目标是 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)磷酸化导致了运输 CD120a(P55)通过两种作用从受体筏到内质网细丝 新的CD120a(P55)相互作用蛋白，TRIP197和pTRIP82；以及2) 内质网细丝磷酸化受体的定位可防止细胞凋亡 内质网中支持生存的信号复合体组装导致的细胞死亡 薄膜。这些假设将通过三个具体目标来解决：1) 确定去磷酸化的CD120a(P55)如何定位于受体筏和 TRIP197的具体作用；2)研究易位的机制 磷酸化CD120a(P55)与内质网细丝的结合及pTRIP82在其中的作用 事件；以及3)研究保护细胞免受 CD120a(P55)磷酸化后的细胞凋亡。这项工作的成果将有 对理解CD120a的地形信号的含义(55页) 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.