G蛋白偶联受体激酶对表皮生长因子信号调控分子机制的初步探讨

发布时间：2018-05-11 22:03

本文选题：G蛋白偶联受体激酶 + 表皮生长因子　；参考：《复旦大学》2005年博士论文

【摘要】：酪氨酸激酶型受体、G蛋白偶联受体和离子通道型受体是细胞表面三类主要受体。酪氨酸激酶型受体(Recptor Tyrosine Kinase,RTK)是一类重要的细胞表面受体家族,由胞外区、单次跨膜螺旋和胞内区组成。RTK的细胞内信号主要由其内在的酪氨酸激酶所介导。RTK在细胞周期、细胞迁移、细胞代谢和细胞增殖分化过程中起重要作用。酪氨酸激酶型受体的信号主要通过受体酪氨酸残基去磷酸化、受体的内吞和降解以及受体羧基末端的丝/苏氨酸残基磷酸化来调控。表皮生长因子受体(Epidermal Growth factor,EGFR)是酪氨酸激酶型受体家族的成员。EGFR在胚胎发育、细胞增殖分化和细胞凋亡起重要作用。EGFR的高表达和EGFR酪氨酸激酶持续激活与肿瘤的发生发展密切相关。 G蛋白偶联受体(GPCR)是另一类重要的细胞膜表面受体超家族。GPCR由一条多肽链构成,其氨基末端在细胞外,羧基末端在细胞内,中间部分肽链形成七个跨膜螺旋结构和连接这七个跨膜螺旋结构的三个细胞内环和三个细胞外环。GPCR的细胞内信号由G蛋白介导,能够转导激素、神经递质、药物、趋化因子以及光线等多种物理的和化学的细胞外信号,这些信号在细胞功能的调节中起重要作用。GPCR信号主要通过其羧基末端的丝/苏氨酸残基磷酸化导致受体与G蛋白解偶联以及受体的内吞和降解来调控。G蛋白偶联受体激酶(GRK)是催化GPCR磷酸化并启动GPCR脱敏的关键蛋白。根据其结构和功能的相似性,GRK分为视觉GRK、GRK2和GRK4三个亚类。从肽链结构上来讲,GRK由高度保守的与受体结合相关的N端,中间催化域和高度变异的具有识别G蛋白βγ亚单位和调节功能的C末端组成。酪氨酸激酶型受体和G蛋白偶联受体信号不是孤立的,而是相互联系的。两者之间存在广泛的对话。G蛋白偶联受体可以反式激活酪氨酸激酶型受体,酪氨酸激酶型受体也可以利用经典的G蛋白偶联受体信号通路的分子来实现其信号转导。文献报道显示,过表达GRK2能增强EGF刺激引起的ERK/MAPK磷酸化,提示GRK对EGF信号有调控作用。但GRK2对EGF信号通路调控的机制目前还不清楚。本研究初步探讨了GRK2对EGF信号通路调控的分子机制。
[Abstract]:Tyrosine kinase receptor, G protein coupled receptor and ion channel receptor are three main receptors on cell surface. Tyrosine kinase receptor Recptor Tyrosine kinase- RTK is a kind of important cell surface receptor family, which consists of extracellular region, single transmembrane helix and intracellular region. The intracellular signal is mainly mediated by its intrinsic tyrosine kinase during cell cycle and cell migration. Cell metabolism and cell proliferation and differentiation play an important role. The signal of tyrosine kinase receptor is mainly regulated by dephosphorylation of receptor tyrosine residues endocytosis and degradation of receptor and phosphorylation of silk / threonine residues at carboxyl end of receptor. Epidermal Growth factor receptor (EGFR) is a member of tyrosine kinase receptor family. EGFR plays an important role in embryonic development, cell proliferation, differentiation and apoptosis. The overexpression of EGFR and the sustained activation of EGFR tyrosine kinase are closely related to the occurrence and development of tumor. G protein-coupled receptor (GPCR) is another important cell membrane surface receptor superfamily. GPCR consists of a polypeptide chain, the amino terminal of which is outside the cell and the carboxyl terminal is in the cell. The middle part of the peptide chain forms seven transmembrane helical structures and the intracellular signal that connects the seven transmembrane helical structures to three cell inner rings and three outer cell rings. GPCR is mediated by G protein and transduces hormones, neurotransmitters, drugs. A variety of physical and chemical extracellular signals, such as chemokines and light, These signals play an important role in the regulation of cell function. GPCR signals are mainly regulated by phosphorylation of the silk / threonine residues at their carboxyl ends leading to uncoupling of receptors to G protein and endocytosis and degradation of receptors. Receptor kinase (GRK) is a key protein that catalyzes GPCR phosphorylation and initiates GPCR desensitization. According to the similarity of its structure and function, GRK can be divided into three subgroups: visual GRK, GRK2 and GRK4. In terms of peptide chain structure, GRK is composed of highly conserved N-terminal associated with receptor binding, intermediate catalytic domain and highly variable C-terminal with recognition of G protein 尾纬 subunit and regulatory function. Tyrosine kinase receptor and G protein coupled receptor signal are not isolated, but are related to each other. There is a wide range of dialogues between the two. G protein-coupled receptors can transactivate tyrosine kinase receptors, and tyrosine kinase receptors can also use the molecules of classical G protein-coupled receptor signaling pathway to realize their signal transduction. It has been reported that overexpression of GRK2 can enhance ERK/MAPK phosphorylation induced by EGF, suggesting that GRK can regulate EGF signal. However, the mechanism of GRK2 regulating EGF signaling pathway is unclear. In this study, the molecular mechanism of GRK2 regulation on EGF signaling pathway was preliminarily investigated.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R33

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