The long-term goal of this work is to understand how cells sense and respond to changes in nutrient availability. We will study a signal transduction cascade in budding yeast important for responding to changes in the level of extracellular inorganic phosphate (the Pho pathway). The transcription factor Pho4 is a target for a phosphate-responsive signal transduction pathway composed of the Pho80-Pho85 cyclin-cyclin dependent kinase (CDK) complex and the CDK inhibitor Pho81. Although we know much about the mechanistic aspects of signaling downstream of Pho80-Pho85, we know little about how changes in phosphate availability are communicated to this kinase, resulting in regulation of its activity. Recently, we made the surprising finding that a metabolite found in all eukaryotic cells, myo-D-inositol heptakisphosphate (IP7), links changes in phosphate availability to changes in the activity of the Pho pathway by controlling the ability of the CDK inhibitor Pho81 to inhibit Pho80-Pho85. IP7 levels increase in response to phosphate limitation and trigger Pho81-dependent inhibition of Pho80-Pho85. This observation provides a unique opportunity to investigate the function of this evolutionarily conserved signaling molecule and to unravel the mechanism by which cells sense changes in phosphate availability. In proposed work, we will investigate the mechanism by which IP7 regulates the activity of the Pho80-Pho85-Pho81 cyclin-CDK-CDK inhibitor complex, determine how changes in phosphate availability lead to changes in IP7 levels, and identify new genes and metabolites involved in inositol polyphosphate metabolism and phosphate signaling. This work will substantially advance our understanding of the mechanisms of signal transduction and provide insights into how cells monitor nutrient levels, basic processes that are misregulated in human diseases and cancer.
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