Pervanadate inhibits mitogen-activated protein kinase kinase-1 in a p38(MAPK)-dependent manner

In baboon smooth muscle cells (SMCs), pervanadate has a biphasic dose-dependent effect on MEK-1 activity. After a 30 min incubation period, low concentrations (1-10 μM) activate, while higher doses (30-100 μM) fail to stimulate MEK-1. One possibility is that higher doses of pervanadate induce an additional signaling pathway that inhibits MEK-1. Three lines of investigations provide support for the conclusion that this inhibitory effect is mediated by p38(MAPK). First, pervanadate induces p38(MAPK) activity at concentrations that fail to activate. MEK-1. Second, pervanadate-stimulated p38(MAPK) activity is maximal after a 10 min incubation, at a time, when MEK-1 activity disappears. Third, addition of the specific p38(MAPK) inhibitor SB203580 preserves MEK-1 activation by 100 μM pervanadate. The inhibitory effect of p38(MAPK) is probably not due to a phosphorylation of MEK-1 although we can not rule out that other p38(MAPK) isoforms such as SAPK3 and SAPK4 may be involved, and may directly phosphorylate and inhibit MEK-1.