A plethora of receptor-mediated signaling pathways initiate production of the lipid messenger phosphatidic acid (PtdOH). Direct activation of phospholipase D (PLD) leads to distinctive molecular species of PtdOH that bind to a variety of cellular targets. A less direct pathway is the receptor-mediated process of phospholipase C (PLC) generation of diacylglycerol with subsequent lipid phosphorylation via diacylglycerol kinase (DGK) leading to downstream production of PtdOH. A third pathway includes direct de novo generation of PtdOH via the Kennedy Pathway. Surprisingly, these pathways from cell surface receptors and constitutively activated pathways leading to PtdOH production are largely uncharacterized. While some of the signaling components such as Arf GTPases, Rho GTPases, protein kinase C, among others have been identified, a well detailed map elucidating the network has not as yet been charted. In this project we use a multi-omics approach to identify key components of these phosphatidic acid signaling pathways looking at the downstream effectors, consequences to membrane lipid composition, intracellular metabolic pathways, innate immune components and other targets of phosphatidic acid signaling. This will provide a basis for understanding how phosphatidic acid signaling contributes to a number of important human pathologies that includes cancer, infectious diseases, and neurodegenerative disorders.
Cell surface receptors signal vital information regarding changes in the environment and mediate communication between cells. This project identifies the cell signaling pathways and metabolic consequences of receptor-mediated phospholipase D activation in parallel with other phosphatidic acid signaling pathways. This project will provide information essential to the development of new therapeutics targeting pathways implicated in cancer, neurodegenerative diseases, and infectious diseases.
| Brown, H Alex; Thomas, Paul G; Lindsley, Craig W (2017) Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov 16:351-367 |
| Mathews, Thomas P; Hill, Salisha; Rose, Kristie L et al. (2015) Human phospholipase D activity transiently regulates pyrimidine biosynthesis in malignant gliomas. ACS Chem Biol 10:1258-68 |
