Phospholipase D signaling

描述（由申请人提供）：磷脂酶D（PLD）及其酶产物，脂质第二信使磷脂酸（PA），在调节多种哺乳动物细胞过程（包括囊泡运输、细胞迁移和细胞生长/增殖）中发挥关键作用。近年来，我们实验室的工作揭示了PLD/PA与哺乳动物雷帕霉素靶蛋白（mTOR）信号网络之间的联系-通过整合生长因子和营养信号来调节细胞生长，并且是针对包括癌症在内的多种人类疾病的药物开发的有吸引力的靶标。这种从PLD到mTOR的途径为PLD参与细胞生长调节和癌症提供了机制，同时暗示了涉及PLD 1的调节网络的存在，该网络尚未被描绘。 在拟议的研究中，我们的目标是剖析PLD 1信号的分子布线，重点是PLD/PA在雷帕霉素敏感的mTOR复合物（mTORC 1）的调节中的作用，以响应促有丝分裂和氨基酸信号。在基于我们最新发现的工作假设的指导下，我们建议研究以下机制：（1）PLD的促有丝分裂调节，（2）PLD的氨基酸调节，和（3）mTORC 1的PA调节。我们在PLD和mTOR信号转导研究方面的经验，我们令人信服的初步数据，以及我们可以使用的独特工具，使我们成为解决这些重要问题的理想人选。在这些研究中获得的知识可能会对我们理解具有机械和临床重要性的信号网络产生重大影响。

DESCRIPTION (provided by applicant): Phospholipase D (PLD) and its enzymatic product, the lipid second messenger phosphatidic acid (PA), are critically involved in the regulation of a wide range of mammalian cellular processes, including vesicle trafficking, cell migration, and cell growth/proliferation. Work from our laboratory in recent years has uncovered a connection between PLD/PA and the mammalian target of rapamycin (mTOR) signaling network - a master regulator of cell growth by integrating growth factor and nutrient signals, and an attractive target for drug development against several human diseases including cancer. This pathway from PLD to mTOR has provided a mechanism for the involvement of PLD in cell growth regulation and cancer, and at the same time has implicated the existence of a regulatory network involving PLD1 that is yet to be delineated. In the proposed studies we aim to dissect the molecular wiring of PLD1 signaling, with an emphasis on the role of PLD/PA in the regulation of the rapamycin-sensitive mTOR complex (mTORC1) in response to mitogenic and amino acid signals. Guided by working hypotheses based on our most recent findings, we propose to investigate the mechanisms underlying (1) mitogenic regulation of PLD, (2) amino acid regulation of PLD, and (3) PA regulation of mTORC1. Our experience with both PLD and mTOR signaling studies, our compelling preliminary data, and the unique tools available to us situate us in an ideal position to tackle those important issues. Knowledge gained in these studies will likely have significant impact on our understanding of a signaling network of mechanistic and clinical importance.