Lysophosphatidic acid (sn-1 acyl 2-hydroxy glycerol 3-phosphate, LPA) is a biologically active extracellular lipid mediator that promotes growth, differentiation, survival and motility in many different cells. Some of these effects are mediated by specific G-protein coupled receptors. LPA has critical roles in a broad range of physiological and pathophysiological processes that include early development, inflammation, thrombosis, atherosclerosis, wound healing, reproduction and cancer. In the first funding period of this award we identified genes encoding phospholipase D (PLD) and Lipid Phosphate Phosphatase (LPP) enzymes. In the second funding period of the award we investigated the structure, regulation and functions of these enzymes identifying key roles in the synthesis and inactivation of LPA. We also characterized a new class of LPP-related (LPR) integral membrane proteins that regulate cellular morphology and cytoskeletal organization. This proposal describes studies to test hypotheses about how these three classes of proteins function to regulate LPA signaling. Lipid binding and mutational studies suggest that a representative LPR protein, LPR1, could a """"""""receptor-like"""""""" mediator of the well-characterized effects of LPA on cell morphology. We will determine the mechanism by which LPR1, regulates the formation of filopodia and related actin-rich structures in fibroblasts and epithelial cancer cells. Secondly we will define the processing, regulation and role in constitutive and agonist promoted LPA production of a lysophosphatidiylcholine (lysoPC)-selective lysophospholipase D that is a potent regulator of cancer cell growth and motility. Finally we will use genetic approaches and novel selective chemical inhibitors to determine the role of lipid phosphate phosphatases (LPPs) in regulation of LPA signaling in mouse vascular smooth muscle cells which are highly responsive to LPA and play a central role in atherosclerosis and vascular responses to injury. The broad long term goal of our research is identify the physiological and pathophysiological functions of LPA signaling. Resolution of the interrelated issues outlined above is central to this goal because it will ultimately lead to the design of pharmacological and genetic strategies to manipulate LPA signaling in vivo.
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