Phospholipase D signaling

描述（由申请人提供）：磷脂酶D （PLD）及其酶促产物，脂质第二信使磷脂酸（PA），在广泛的哺乳动物细胞过程的调节中起关键作用，包括囊泡运输、细胞迁移和细胞生长/增殖。近年来，我们实验室的工作发现了PLD/PA与哺乳动物雷帕霉素靶点（mTOR）信号网络之间的联系，雷帕霉素是通过整合生长因子和营养信号来调节细胞生长的主要靶点，也是治疗包括癌症在内的几种人类疾病的药物开发的一个有吸引力的靶点。从PLD到mTOR的这一途径为PLD参与细胞生长调控和癌症提供了一种机制，同时也暗示存在一个涉及PLD1的调控网络，但尚未被描述清楚。在我们提出的研究中，我们的目标是剖析PLD1信号的分子布线，重点是PLD/PA在调节雷帕霉素敏感的mTOR复合物（mTORC1）响应有丝分裂和氨基酸信号中的作用。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的有丝分裂调节，(2)PLD的氨基酸调节，(3)mTORC1的PA调节。我们在PLD和mTOR信号研究方面的经验，令人信服的初步数据，以及我们可用的独特工具，使我们处于解决这些重要问题的理想位置。在这些研究中获得的知识可能会对我们对信号网络的机制和临床重要性的理解产生重大影响。

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.