CSF-1R Regulation of Type I PIP5K

什里夫波特路易斯安那州立大学健康科学中心的J. Nathan Davis博士获得了一项资助，用于研究磷脂酰肌醇4-磷酸5-激酶（mPIP5K-Ibeta）的β亚型，该酶参与膜脂代谢，磷脂酰肌醇（PtdIns）。PtdIns调节多种细胞过程，包括存活和增殖、受体内化、膜运输、分泌和细胞结构重塑。这种功能的多样性是由于特定的PtdIns激酶在肌醇环上的特定位点添加磷酸基团。戴维斯博士的研究旨在确定激素和生长因子调节mPIP5K-Ibeta活性的机制。先前的研究表明，mPIP5K-Ibeta是集落刺激因子-1受体（CSF-1R）和表皮生长因子受体（EGFR）激活生长因子受体的适当内化所必需的。本研究的目的之一是确定mpip5k - β与这些生长因子受体之间的分子相互作用。第二个系列的实验旨在检验另一种膜脂，磷脂酸（PA）在mPIP5K-Ibeta调节中的作用。戴维斯博士进行的研究涉及一种酶的基本调节，这种酶是细胞pttin代谢的核心。所有有核细胞（动物、植物和真菌细胞）都表达I型磷脂酰肌醇4-磷酸5激酶的同工型，而PtdIns的代谢对这些细胞至关重要。PtdIns代谢的无所不在和本质使得PtdIns合成成为通过设计特异性抑制或激活某些类型的这些酶的化学物质产生细胞杀伤剂的主要目标。以真菌酶为靶点，可以生产出在食品保存、农业对抗植物和动物真菌感染或医疗保健抗真菌化疗中有用的制剂。植物特异酶的小分子抑制剂是一种对其他生物无毒性的潜在除草剂。然而，在实现这些目标之前，必须对所有涉及的酶进行详细的了解。

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.