ATTENUATION OF LPA-MEDIATED CALCIUM SIGNALING AND INOSITOL POLYPHOSPHATE PRODUCTION IN RAT-1 FIBROBLASTS TRANSFORMED BY THE V-SRC ONCOGENE

Alterations in cellular signaling underlie the trans forming actions o f many oncogenes. The vsrc oncogene tyrosine kinase, pp60(vsrc), is kn own to alter multiple signal transduction pathways, including those in volving phosphatidylinositol (PI) metabolism. In this study, we invest igated the effects of vsrc-transforrmation on lysophosphatidic acid (L PA) receptor coupling to intracellular free calcium [Ca2+](i) and PI t urnover in rat-1 fibroblasts. In normal rat-1 cells, LPA rapidly eleva ted [Ca2-](i) (EC50 = 10nM). In contrast, the ability of LPA to mobili ze calcium was markedly attenuated in rat-1-vsrc cells. Further study revealed that the LPA-mediated generation of inositol (1,4,5)P-3 and o ther inositol polyphosphates was also markedly attenuated in the vsrc- transformed cells. Although LPA caused a transient reduction in the le vel of PI(4,5)P-2 in normal rat-1 cells, the agonist elevated the leve l of PI(4,5)P-2 in the vsrc-transformed cells. These findings demonstr ate that vsrc-transformation alters the coupling of LPA receptors to P I turnover and calcium signaling in rat-1 cells, and point to G protei n-coupled receptor systems as targets for modulation by the vsrc kinas e, (C) 1998 Academic Press.