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.
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.
| Fang, Yimin; Hill, Cristal M; Darcy, Justin et al. (2018) Effects of rapamycin on growth hormone receptor knockout mice. Proc Natl Acad Sci U S A 115:E1495-E1503 |
| Dutta, Debapriya; Lai, Kuan-Yu; Reyes-Ordoñez, Adriana et al. (2018) Lanthionine synthetase C-like protein 2 (LanCL2) is important for adipogenic differentiation. J Lipid Res 59:1433-1445 |
| Kim, Ik-Jung; Lee, Jeongmin; Oh, Seung J et al. (2018) Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. Cell Host Microbe 23:583-593.e8 |
| Li, Xiaoguang; Edwards, Marc; Swaney, Kristen F et al. (2018) Mutually inhibitory Ras-PI(3,4)P2 feedback loops mediate cell migration. Proc Natl Acad Sci U S A 115:E9125-E9134 |
| Arif, Abul; Terenzi, Fulvia; Potdar, Alka A et al. (2017) EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542:357-361 |
| Yoon, Mee-Sup; Son, Kook; Arauz, Edwin et al. (2016) Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling. Cell Rep 16:1510-1517 |
| Arauz, Edwin; Aggarwal, Vasudha; Jain, Ankur et al. (2016) Single-Molecule Analysis of Lipid-Protein Interactions in Crude Cell Lysates. Anal Chem 88:4269-76 |
| Yoon, Mee-Sup; Rosenberger, Christina L; Wu, Cong et al. (2015) Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid. Mol Cell 58:549-56 |
| Jain, Ankur; Arauz, Edwin; Aggarwal, Vasudha et al. (2014) Stoichiometry and assembly of mTOR complexes revealed by single-molecule pulldown. Proc Natl Acad Sci U S A 111:17833-8 |
| Zeng, Min; van der Donk, Wilfred A; Chen, Jie (2014) Lanthionine synthetase C-like protein 2 (LanCL2) is a novel regulator of Akt. Mol Biol Cell 25:3954-61 |
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