Phospholipase D signaling

描述(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)，在调节哺乳动物的广泛细胞过程中起重要作用，包括囊泡运输、细胞迁移和细胞生长/增殖。我们实验室近年来的工作揭示了PLD/PA与哺乳动物雷帕霉素靶点(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，并成为治疗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，同时也暗示了涉及PLD1的调控网络的存在，该网络尚未被描述。在拟议的研究中，我们旨在剖析PLD1信号的分子连接，重点是PLD/PA在调节雷帕霉素敏感的mTOR复合体(MTORC1)对有丝分裂和氨基酸信号的反应中所起的作用。在基于我们最新发现的工作假说的指导下，我们建议研究(1)PLD的有丝分裂调节，(2)PLD的氨基酸调节，以及(3)PA对mTORC1的调节的机制。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理解具有机制和临床重要性的信号网络产生重大影响。 公共卫生相关性：哺乳动物细胞生长和增殖的调控是细胞生物学中的一个基本问题，直接关系到对人类疾病(如癌症)的理解和抗击，而磷脂酶D(PLD)及其酶产物--脂质第二信使磷脂酸(PA)--在调控包括细胞生长和增殖在内的广泛哺乳动物细胞过程中起着至关重要的作用。我们实验室近年来的工作发现了PLD1/PA与另一个主要的信号网络之间的联系，即mTOR，后者是治疗包括癌症在内的几种人类疾病的药物开发的有吸引力的靶点。我们在解剖这一重要分子网络方面的持续努力可能有助于对细胞生长调控的总体理解，并影响未来的抗癌治疗策略。

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. PUBLIC HEALTH RELEVANCE: The regulation of mammalian cell growth and proliferation is a fundamental question in cell biology directly relevant to the understanding and combating of human diseases such as cancer, and 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 cell growth and proliferation. Work from our laboratory in recent years has uncovered a connection between PLD1/PA and another major signaling network in the regulation of cell growth in response to environmental cues-namely mTOR, the latter being an attractive target for drug development against several human diseases including cancer. Our continued efforts in dissecting this essential molecular network will likely contribute to the general understanding of cell growth regulation, and impact future therapeutic strategies against cancer.