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 mu M) activate, while higher doses (30-100 mu M) fail to stimulate MEK-1. One possibility is that higher doses of p ervanadate 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 i nduces 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 mu M pervanadate. The inhibitory effect of p38(MAPK ) is probably not due to a phosphorylation of MEK-1 although we can no t rule out that other p38(MAPK) isoforms such as SAPK3 and SAPK4 may b e involved, and may directly phosphorylate and inhibit MEK-1. (C) 1998 Federation of European Biochemical Societies.