Retracted: Lipid Phosphate Phosphatase-1 And Ca2+ Control Lysophosphatidate Signaling Through Edg-2 Receptors (Retracted Article. See Vol 278, Pg 38104, 2003)

The serum-derived phospholipid growth factor, lysophosphatidate (LPA), activates cells through the EDG family of G protein-coupled receptors, The present study investigated mechanisms by which dephosphorylation of exogenous LPA by lipid phosphate phosphatase-1 (LPP-1) controls cell signaling. Overexpressing 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 diminished responses, including cAMP, Ca2+, activation of phospholipase D and ERK, DNA synthesis, and cell division. Conversely, decreasing LPP-1 expression increased net LPA association, ERK stimulation, and DNA synthesis. Whereas changing LPP-1 expression did not alter the apparent K-d and B-max for LPA 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 activation to the nanomolar range. Hence the Ca2+ dependence of the apparent K-d values explains the long-standing discrepancy of why micromolar LPA is often needed to activate cells at physiological Ca2+ levels. In addition, the work demonstrates that LPP-1 can regulate specific LPA association with cells without significantly depleting bulk LPA concentrations in the extracellular medium. This identifies a novel mechanism for controlling EDG-2 receptor activation.