ACTIVATION OF PROTEIN-KINASE-C BY LYSOPHOSPHATIDIC ACID - DEPENDENCE ON COMPOSITION OF PHOSPHOLIPID-VESICLES

Lysophosphatidic acid (LPA) has attracted recent attention as a major serum-derived regulator implicated in responses to vascular injury and inflammation, in tumour invasiveness and in neuronal signalling and r emodelling. Although the possibility of a specific G-protein-coupled L PA receptor protein has been suggested, characterization of such a rec eptor is lacking. Since LPA can activate protein kinase C (PKC) pathwa ys in many cells and PKC activators mimic many LPA effects, the possib ility of more direct LPA effects on PKC was investigated. Phosphatidyl choline (PC)/phosphatidylserine (PS)/diacylglycerol (DAG) lipid vesicl es of defined acyl chain composition were used to activate the enzyme. At total concentrations of saturated PC/PS+DAG vesicles (2-3 mM) that provided maximal PKC activation, 1-10 mol% [18:1]-LPA led to a furthe r approx. 2-fold activation of PKC alpha. At lower lipid concentration s, a greater increase was observed with LPA concentrations up to 16-20 mol%. Higher concentrations of LPA were inhibitory. The LPA activatio n of PKC was dependent on the presence of DAG, PS and Ca2+. [18:1]-Lys ophosphatidylcholine produced similar PKC activation in PC/PS/DAG vesi cles. [14:0]-LPA was less effective, and longer-chain saturated lysoli pids were ineffective. In unsaturated PC/PS vesicles, very little to n o effect of LPA was discernable. These results suggest that physiologi cally or pathologically relevant concentrations of LPA can contribute to PKC activation depending on the composition of the lipid membrane. We hypothesize that LPA may affect the formation of lipid domains that are recognized by the enzyme.