P38 MI TOG E N -ACT I VAT E I) KINASE AND C-JlJN TERMINAL KINASE, BUT NOT EXTRACELLULAR SIGNAL-REGULATED KINASE, ARE REQUIRED FOR THE LPA- INDUCED MIGRATION OF GLIOMA CELLS / Шинэ санаа Шинэ нээлт

ABSTRACT

A potential role for lysophosphatidie acid (LPA) in the regulation of malignant diseases has been widely considered. Migratory response to LPA in glioma cells was almost completely inhibited by either pertussis toxin, LPA1 receptor antagonists including Ki 16425, or an inhibitor of phosphatidylinositol 3-kinase (PI3K) wortmannin. LPA action on migration was also suppressed, though incompletely by several specific inhibitors for intracellular signaling pathways such as Racl, p38 mitogen- activatcd protein kinase (p38 MAPK) and c-Jun terminal kinase (JNK), but not extracellular signal-regulated kinase. Nearly complete inhibition of the migration response to LPA, however, required simultaneous inhibition of both the p38MAPK and JNK pathways. Inhibition of Racl suppressed JNK but not p38MAPK, and dominant-negative form of Cdc42 abrogated p38MAPK activity. These findings suggest that, in glioma cells, the PI3K/Cdc42/ p38MAPK and PI3K/Racl/JNK pathways arc equally important for LPA1 receptor- mediated migration.