RECEPTOR INTERACTION WITH GTP-REGULATORY PROTEINS

异源三聚体GTP结合蛋白家族，称为G 蛋白质，通过偶联细胞表面受体来控制 细胞内信号转导途径。G蛋白偶联受体 具有特征性的七跨膜结构（STM）。的 STM受体的细胞外和膜结构域的序列不同， 允许选择性结合不同的配体，包括光子，离子， 气味剂，分子如乙酰胆碱和儿茶酚胺，肽和 蛋白酶STM受体与G 蛋白质家族。已知的G蛋白可分为四类 基于序列和功能同源性的家族。已知效应器 G蛋白包括腺苷酸环化酶、磷脂酰肌醇磷脂酶 C β、cGMP-磷酸二酯酶和特异性离子通道。G的列表 蛋白质效应物肯定会增长，并可能包括特定的酪氨酸 激酶、磷酸酶和Na+/H+反向转运蛋白。许多人类 现在已经发现疾病是由特定的STM突变引起的， 受体和G蛋白α亚单位。在甲状腺和脑垂体的增益 受体和Ga多肽的功能突变导致 功能亢进的腺瘤STM神经肽受体也是 参与刺激血管平滑肌细胞的增生， 结肠和肺的上皮细胞。 该建议的目的是确定信号转导途径 由控制细胞增殖的G蛋白调节， 分化表型G蛋白刺激的Ras GTP负载是一个主要的 有丝分裂的STM受体调节的组成部分。G蛋白 将定义Ras激活的调节。G的整合 生长因子受体酪氨酸激酶蛋白调节信号 信号转导通路和Ras功能的参与， 过程也将被描述。这些研究将包括 非Ras小G蛋白（即Rac）的STM受体调节的分析 和Rho）和控制细胞凋亡的顺序蛋白磷酸化途径。 不同MAP激酶的活性。 G蛋白偶联受体可以 正、负调节酪氨酸激酶的反应性 刺激有丝分裂信号。积极或消极的调节 STM受体的酪氨酸激酶刺激信号由 G蛋白偶联的多种亚型的细胞特异性表达 腺苷酸环化酶和磷脂酶C β。这些研究 将定义调节被改变的信号转导通路 由于STM受体和Ga α亚基突变或改变， 表情这将有可能治疗人类疾病造成的， G蛋白和/或酪氨酸激酶功能的获得或丧失， 选择性地操纵特定反应途径的活性， 由这些不同的受体系统调节。

The family of heterotrimeric GTP-binding proteins, referred to as G proteins, function by coupling cell surface receptors to the control of intracellular signal transduction pathways. G protein-coupled receptors have a characteristic seven transmembrane structure (STM). The extracellular and membrane domains of STM receptors vary in sequence to allow selective binding of different ligands including photons, ions, odorants, molecules like acetylcholine and catecholamines, peptides and proteases. The STM receptors differentially couple to members of the G protein family. The known G proteins can be categorized into four families based on sequence and functional homologies. Known effectors for G proteins include adenylyl cyclases, phosphotidylinositol phospholipase Cbeta, cGMP-phosphodiesterase and specific ion channels. The list of G protein effectors is certain to grow and may include specific tyrosine kinases, phosphatases and the Na+/H+ antiporter. A number of human diseases have now been found to result from mutation of specific STM receptors and G protein alpha subunits. In the thyroid and pituitary gain of function mutations in receptors and the Galpha(s) polypeptide result in hyperfunctioning adenomas. STM neuropeptide receptors are also involved in stimulating hyperplasia of vascular smooth muscle cells and epithelial cells of the colon and lung. The aim of this proposal is to define the signal transduction pathways regulated by G proteins that control cell proliferation and the differentiated phenotype. G protein stimulated Ras GTP loading is a major component of STM receptor regulation of mitogenesis. The G protein regulation of Ras activation will be defined. The integration of G protein-regulated signaling with growth factor receptor tyrosine kinase signal transduction pathways and the involvement of Ras function in this process will also be characterized. These studies will include the analysis of STM receptor regulation of non-Ras small G proteins (i.e. Rac and Rho) and sequential protein phosphorylation pathways controlling the activity of different MAP kinases. G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase stimulated mitogenic signals. The positive or negative regulation of tyrosine kinase stimulated signals by STM receptors is dictated by the cell specific expression of the numerous isoforms of G protein-coupled effectors like adenylyl cyclase and phospholipase Cbeta. These studies will define the signal transduction pathways whose regulation is altered as a result of STM receptor and Galpha subunit mutation or change in expression. It will be possible to treat human diseases resulting from gain or loss of function of G protein and/or tyrosine kinases by selectively manipulating the activity of specific response pathways regulated by these different receptor systems.