Lysophosphatidic acid-induced mitogenesis is regulated by lipid phosphate phosphatases and is Edg-receptor independent

Lysophosphatidic acid (LPA) is an extracellular signaling mediator with a b road range of cellular responses. Three G-protein-coupled receptors (Edg-2, -4, and -7) have been identified as receptors for LPA. In this study, the ectophosphatase lipid phosphate phosphatase 1 (LPP1) has been shown to down -regulate LPA-mediated mitogenesis. Furthermore, using degradation-resistan t phosphonate analogs of LPA and stereoselective agonists of the Edg recept ors we have demonstrated that the mitogenic and platelet aggregation respon ses to LPA are independent of Edg-2, -4, and -7. Specifically, we found tha t LPA degradation is insufficient to account for the decrease in LPA potenc y in mitogenic assays, and the stereoselectivity observed at the Edg recept ors is not reflected in mitogenesis. Additionally, RH7777 cells, which are devoid of Edg-2, -4, and -7 receptor mRNA, have a mitogenic response to LPA and LPA analogs. Finally, we have determined that the ligand selectivity o f the platelet aggregation response is consistent with that of mitogenesis, but not with Edg-2, -4, and -7.