Role of STAT proteins in MAPK signal transduction pathways

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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.