Pervanadate inhibits mitogen-activated protein kinase kinase-1 in a p38MAPK-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 microM) activate, while higher doses (30-100 microM) 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 p38MAPK. First, pervanadate induces p38MAPK activity at concentrations that fail to activate MEK-1. Second, pervanadate-stimulated p38MAPK activity is maximal after a 10 min incubation, at a time, when MEK-1 activity disappears. Third, addition of the specific p38MAPK inhibitor SB203580 preserves MEK-1 activation by 100 microM pervanadate. The inhibitory effect of p38MAPK is probably not due to a phosphorylation of MEK-1 although we can not rule out that other p38MAPK isoforms such as SAPK3 and SAPK4 may be involved, and may directly phosphorylate and inhibit MEK-1.