CSF-1R Regulation of Type I PIP5K

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A grant has been awarded to Dr. J. Nathan Davis of Louisiana State University Health Sciences Center in Shreveport for the study of the beta isoform of phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta), an enzyme involved in the metabolism of the membrane lipid, phosphatidylinositol (PtdIns). PtdIns regulates diverse cellular processes including survival and proliferation, receptor internalization, membrane trafficking, secretion, and remodeling of cell structure. Such diversity of function is due to the addition of phosphate groups at specific sites on the inositol ring by specific PtdIns kinases. Dr. Davis's studies are designed to define the mechanisms by which hormones and growth factors regulate the activity of mPIP5K-Ibeta. Previous studies have shown that mPIP5K-Ibeta is required for the proper internalization of activated growth factor receptors using both the colony stimulating factor-1 receptor (CSF-1R) and the epidermal growth factor receptor (EGFR). One aim of this proposal is to define the molecular interactions between mPIP5K-Ibeta and these growth factor receptors. A second series of experiments are designed to examine the role of another membrane lipid, phosphatidic acid (PA), in the regulation of mPIP5K-Ibeta. The studies undertaken by Dr. Davis concern the basic regulation of an enzyme that is central to cellular PtdIns metabolism. All nucleated cells (animal, plant and fungal cells) express isoforms of the type I phosphatidylinositol 4-phosphate 5-kinase and PtdIns metabolism is essential to these cells. The ubiquitous and essential nature of PtdIns metabolism makes PtdIns synthesis a prime target for generation of cytocidal agents through the design of chemicals that specifically inhibit or activate certain classes of these enzymes. The targeting of fungal enzymes could produce agents useful in food preservation, the agricultural industry to combat fungal infections of plants and animals or in healthcare for antifungal chemotherapy. Small molecule inhibitors of plant specific enzymes are potential herbicides lacking toxicity to other organisms. However, detailed understanding of all the enzymes involved must be obtained before these goals are realized.