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.
Daum
G
G
Department of Surgery, University of Washington, Seattle 98195-6410, USA. daum@u.washington.edu
Kalmes
A
A
Levkau
B
B
Wang
Y
Y
Davies
M G
MG
Clowes
A W
AW
D051698:Activating Transcription Factor 2; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D010215:Papio; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C076715:pervanadate; D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580