TNFA RECEPTOR CD120A INDUCED SIGNALING IN MACROPHAGES

描述(改编自申请者的抽象和具体目标)： 肿瘤坏死因子α(TNFa)与许多人类 疾病过程，尤其是涉及肺的巨噬细胞 似乎是重要的目标细胞。TnFa被细胞识别 表面受体CD120a(P55)和CD120b(P75)。结扎术和 CD120a(P55)的聚集是诱导 大多数细胞对TNFa的反应包括对一氧化氮的诱导 巨噬细胞表达氧化物和胰岛素样生长因子-1。 据报道，几种信号转导机制包括 响应于激活的TNFa而被激活，该激活包括 介导p42mapk/ERK2的激活。目前尚不清楚这是如何实现的 激酶级联反应与CD120a偶联(P55)。据推测， 通过CD120a(P55)的信号是由磷蛋白pp95启动的 和/或pp120，通过它们与 CD120a的胞内结构域(P55)，使 受体和远端的激酶信号通过RAS级联。具体的 目的是：1)纯化和克隆磷酸化蛋白pp95和pp120， 它们与胞内结构域(ICD)密切相关 CD120a(P55)；2)研究pp95和pp120的功能 定义CD120a(55页)ICD内相互作用的区域(S) 用pp95和pp120；3)测定上游激酶(S)和 负责激活p42mapk/ERK2的信号组件。

DESCRIPTION (Adapted from the applicant's abstract and specific aims): Tumor necrosis factor alpha (TNFa) has been implicated in many human disease processes especially those involving the lung as macrophages appear to be important target cells. TNFa is recognized by the cell surface receptors CD120a, (p55) and CD120b (p75). Ligation and aggregation of CD120a (p55) are necessary for the induction of the majority of cellular responses to TNFa including the induction of nitric oxide and insulin-like growth factor-1 expression by macrophages. Several signal transduction mechanisms have been reported to be activated in response to activated TNFa including a kinase cascade that mediates the activation of p42mapk/erk2. It is not known how this kinase cascade is coupled to CD120a (p55). It is hypothesized that signalling through CD120a (p55) is initiated by the phosphoproteins pp95 and/or pp120 which, through their intrinsic association with the intracellular domain of CD120a (p55), enable communication between the receptor and the distal kinase signaling cascade via RAS. The specific aims are: 1) to purify and clone the phosphoproteins, pp95 and pp120, that are constitutively associated with the intracellular domain (ICD) of CD120a (p55); 2) to investigate the functions of pp95 and pp120 and to define the region(s) within the ICD of CD120a (p55) that interact with pp95 and pp120; and 3) to determine the upstream kinase(s) and signalling components responsible for activating p42mapk/erk2.