NOVEL SIGNALING PATHWAYS FOR ANGIOTENSIN II IN THE HEART

描述(改编自《研究人员摘要》)：血管紧张素II 肾素-血管紧张素系统的效应肽，调节体积和 电解质稳态，参与心脏和血管细胞 人类和其他物种的生长。这个系统，一直被保存下来 在整个进化过程中，它在心脏和血管中扮演着重要的角色 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AT1，G-蛋白(鸟苷酸结合)介导 蛋白质)偶联受体。除了与传统的 G蛋白的信号转导途径，AT1受体是最近被发现的 提高几种细胞内酪氨酸的磷酸化水平 衬底，包括STAT(信号传感器和激励器 转录)家族的新转录因子，在大鼠心脏 成纤维细胞、心肌细胞和血管平滑肌细胞与AT1a受体 转基因中国仓鼠卵巢(CHO)细胞。这很可能是因为 途径在血管紧张素II介导的基因调控中的作用，心脏和 血管细胞生长和炎症反应。AT1受体， 它缺乏固有的酪氨酸激酶活性，已经在大鼠身上显示出来 血管平滑肌细胞和心肌细胞与JAK2，a Janus家族成员(JAK)，与酪氨酸有关 统计数据的磷酸化。这些发现，正如最初为 细胞因子(白介素类和干扰素类)提示AT1受体 可能包含JAK2的对接站点。猪瘟病毒的氨基酸序列分析 AT1受体，也暗示了与Src激酶潜在的结合基序， STAT3和SH-PTP1D(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，近端 这些新信号转导的偶联和激活机制 途径，仍有待阐明。利用分子、生化和 细胞方法，PI将确定AT1的结构区域 负责信号蛋白和胞浆相互作用的受体 酪氨酸激酶和确定G蛋白在募集和 激活JAK-STAT组件。这些研究对以下方面具有重要意义 阐明血管紧张素II在靶细胞中的作用 完全理解七螺旋的分子信号转导 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.