NOVEL SIGNALING PATHWAYS FOR ANGIOTENSIN II IN THE HEART

描述（改编自研究者摘要）：血管紧张素II， 肾素-血管紧张素系统的效应肽，调节体积， 电解质稳态，并参与心脏和血管细胞 在人类和其他物种中生长。 这个系统， 在整个进化过程中，在心脏和血管中起着重要作用。 与高血压、冠心病、心肌炎相关的病理学 和充血性心力衰竭 血管紧张素II的这些关键作用是 主要通过AT 1、G蛋白（鸟苷酸结合）介导 蛋白）偶联受体。 除了耦合到传统的 G蛋白信号转导途径，AT 1受体最近被证明是 增加几种细胞内酪氨酸磷酸化， 底物，包括STAT（信号转导和激活剂， 转录）家族的新转录因子，在大鼠心脏 成纤维细胞、肌细胞和血管平滑肌细胞，以及AT 1A受体 转染的中国卵巢癌（CHO）细胞。 这很可能 途径在血管紧张素II介导的基因调节、心脏和 血管细胞生长和炎症反应。 AT 1受体， 缺乏内在酪氨酸激酶活性， 血管平滑肌细胞和心肌细胞，与Jak 2相关， Janus激酶家族（JAK）的成员，参与酪氨酸 STATs的磷酸化。 这些发现，正如最初描述的那样 细胞因子（白细胞介素和干扰素γ），表明AT 1受体 可能包含Jak 2的对接点。 氨基酸序列分析 AT 1受体，也提示了Src激酶的潜在结合基序， Stat 3和SH-PTP 1D（一种酪氨酸磷酸酶），所有这些都是 JAK-STAT途径。 然而，对于G蛋白受体， 这些新的信号转导的耦合和激活机制 路径，仍有待阐明。 利用分子、生物化学和 细胞的方法，PI将确定AT 1的结构区域 一种负责信号蛋白和细胞溶质相互作用的受体 酪氨酸激酶，并确定G蛋白在募集和 激活JAK-STAT组件。 这些研究对于 阐明血管紧张素II在靶细胞中介导的作用， 对七螺旋的分子信号传导的完整理解 受体超家族。

DESCRIPTION (Adapted from Investigator's Abstract): Angiotensin II, the effector peptide of the renin-angiotensin system, regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. These critical actions of angiotensin II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1A receptor transfected Chinese Hamster Ovary (CHO) cells. It is likely that this pathway has a role in angiotensin II mediated gene regulation, cardiac and vascular cellular growth and inflammatory responses. The AT1 receptor, which lacks intrinsic tyrosine kinase activity, has been shown in rat vascular smooth muscle cells and cardiomyocytes, to associate with Jak2, a member of the Janus family of kinases (JAK), implicated in the tyrosine phosphorylation of the STATs. These findings, as originally described for cytokines (interleukins and interferon gamma), suggest that the AT1 receptor may contain a docking site for Jak2. Analysis of the amino acid sequence of the AT1 receptor, also suggests potential binding motifs for Src kinase, Stat3, and SH-PTP1D (a tyrosine phosphatase), all of which are components of the JAK-STAT pathway. However, for G-protein receptors, the proximal mechanisms for coupling and activation of these novel signal transduction pathways, remain to be elucidated. Utilizing molecular, biochemical and cellular approaches, the PI will determine the structural regions of the AT1 receptor responsible for the interaction of signaling proteins and cytosolic tyrosine kinases and define the role of G-proteins in the recruitment and activation of the JAK-STAT components. These studies are important for elucidating angiotensin II mediated actions in target cells and for a more complete understanding of the molecular signaling of the heptahelical superfamily of receptors.