Role of STAT proteins in MAPK signal transduction pathways

描述（由申请人提供）：G蛋白和MAP激酶（促分裂原活化蛋白激酶，MAPK）介导的信号转导途径与细胞生长和分化的调节以及癌症、心脏肥大和肥胖等疾病的发生有关。这些信号蛋白和STAT（信号转导和转录激活因子）蛋白已在广泛的真核生物中被鉴定，但STAT蛋白在G蛋白/MAPK途径中的作用仍有待确定。拟议的研究将调查STAT蛋白在MAPK突变体中的调控，因为最近的研究表明MAPK和STAT功能在组织特异性基因表达的调控中存在重叠。STAT蛋白通过MAPK途径的调节将被检查涉及STAT蛋白上的MAPK特异性对接和磷酸化位点的直接相互作用以及涉及cAMP信号传导变化的间接相互作用。这些研究将确定STAT蛋白在控制基因表达和细胞分化的G蛋白/MAPK通路中的重要性和特异性。这些研究将挑战以前的MAPK和STAT蛋白在不同途径中发挥作用的信号传导模式。 公共卫生相关性：MAP激酶通过调节其他信号蛋白如转录因子来协调细胞生长和分化。这些信号通路的改变可导致肿瘤发生、心脏病和几种发育性疾病。本研究将研究MAPK调节STAT蛋白，一类转录因子以前没有与MAPK信号通路。本研究的结果将为MAPK通路的调控和相关疾病的治疗提供重要的见解。

DESCRIPTION (provided by applicant): Signal transduction pathways mediated by G proteins and MAP kinases (mitogen activated protein kinases, MAPKs) have been associated with the regulation of cell growth and differentiation and the development of diseases such as cancer, cardiac hypertrophy, and obesity. These signaling proteins and STAT (signal transducer and activator of transcription) proteins have been identified in a wide range of eukaryotes but the role of STAT proteins in G protein/MAPK pathways remains to be determined. The proposed research will investigate the regulation of STAT proteins in MAPK mutants in Dictyostelium development because recent studies suggest an overlap in MAPK and STAT function in the regulation of tissue specific gene expression. The regulation of STAT proteins through MAPK pathways will be examined for direct interactions involving MAPK-specific docking and phosphorylation sites on STAT proteins and for indirection interactions involving changes in cAMP signaling. These studies will determine the importance and specificity of STAT proteins in G protein/MAPK pathways that control gene expression and cell differentiation. These studies will challenge previous signaling paradigms of MAPKs and STAT proteins functioning in separate pathways. PUBLIC HEALTH RELEVANCE: MAP kinases coordinate cell growth and differentiation by regulating other signaling proteins such as transcription factors. Alterations in these signaling pathways can lead to oncogenesis, heart disease, and several developmental diseases. This study will examine MAPK regulation of STAT proteins, a class of transcription factors not previously associated with MAPK signaling pathways. The results of this research will provide important insights into the regulation of MAPK pathways and the treatment of related diseases.