Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signalingthrough EDG-2 receptors

The serum-derived phospholipid growth factor, lysophosphatidate (LPA), acti vates cells through the EDG family of G protein-coupled receptors, The pres ent study investigated mechanisms by which dephosphorylation of exogenous L PA by lipid phosphate phosphatase-1 (LPP-1) controls cell signaling. Overex pressing LPP-1 decreased the net specific cell association of LPA with Rats fibroblasts by approximately 50% at 37 degrees C when less than 10% of LPA was dephosphorylated. This attenuated cell activation as indicated by dimi nished responses, including cAMP, Ca2+, activation of phospholipase D and E RK, DNA synthesis, and cell division. Conversely, decreasing LPP-1 expressi on increased net LPA association, ERK stimulation, and DNA synthesis. Where as changing LPP-1 expression did not alter the apparent K-d and B-max for L PA binding at 4 degrees C, increasing Ca2+ from 0 to 50 mu M increased the K-d from 40 to 900 nM. Decreasing extracellular Ca2+ from 1.8 mM to 10 mu M increased LPA binding by 20-fold, shifting the threshold for ERK activatio n to the nanomolar range. Hence the Ca2+ dependence of the apparent K-d val ues explains the long-standing discrepancy of why micromolar LPA is often n eeded to activate cells at physiological Ca2+ levels. In addition, the work demonstrates that LPP-1 can regulate specific LPA association with cells w ithout significantly depleting bulk LPA concentrations in the extracellular medium. This identifies a novel mechanism for controlling EDG-2 receptor a ctivation.