Activation of epidermal growth factor receptor is responsible for pervanadate-induced phospholipase D activation

다국어 초록 (Multilingual Abstract)

Pervanadate, a complex of vanadate and H2O2, has an insulin mimetic effect, and acts as an inhibitor of protein tyrosine phosphatase. Pervanadate-in-duced phospholipase D (PLD) activation is known of cellular proteins and protein kinase C (PKC) ac-tivation, and yet underlying molecular mechani-sms are not clearly understood. Here, we inves-tigated the signaling pathway of pervanadate-in-duced PLD activation in Rat2 fibroblasts. Per-vanadate increased PLD activity in dose- and time- dependent manner. Protein tyrosine kinase inhi-bitor, genistein, blocked PLD activation. Interes-tingly, AG-1478, a specific inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR) blocked not only the PLD activation com-pletely but also phosphorylation of p38 mitogen- 1295, an inhibitor specific for the tyrosine kinase activity of pletlet drived growth factor receptor (PDGFR) did not show any effect on the PLD activation by pervanadate. We further found that pervanadate increased phosphorylation levels of p38, extracelular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK). SB203580, a p38 MAPK inhibitor, blocked the PLD activation completely. However, the inhibitions of ERK by the treatment of PD98059 or of JNK by the overexpres-sion of JNK interacting peptide JBD did not show tion. Inhibition or down-regulation of PKC did not alter the pervanadate-induced PLD activation in Rat2 cels. Thus, these results suggest that per-vanadate-induced PLD activation is coupled to the transactivation of EGFR by pervanadate resulting in the activation of p38 MAP kinase.