DEPHOSPHORYLATION AND INACTIVATION OF THE MITOGEN-ACTIVATED PROTEIN-KINASE BY A MITOGEN-INDUCED THR TYR PROTEIN PHOSPHATASE

The activation of extracellular signal-regulated kinase (ERK) or mitog en-activated protein kinase (MAPK) by a dual specific kinase, MEK (MAP K or ERK kinase), is a critical event in the mitogenic signal transduc tion pathway. However, little is known about the mechanism of ERK inac tivation, which occurs after stimulation. In this report, we demonstra ted that a dual specific protein phosphatase, HVH1 (human VH1 phosphat ase homolog) whose expression is induced by mitogenic growth factors, specifically inactivates ERK. When several phosphoproteins were tested for recombinant HVH1, only MEK-activated ERK1 was dephosphorylated. H VH1 selectively dephosphorylated threonine and tyrosine residues but n ot serine residues of the activated ERK1. Inactivation of ERK1 by HVH1 could be reversed by MEK, suggesting that HVH1 dephosphorylates the s ame residues that are recognized and phosphorylated by MEK. Our result s suggest that mitogenic growth factors transiently activate ERK (peak at 5 min followed by a rapid decline) by temporally activating MEK (t he on signal) and inducing the expression of HVH phosphatase (the off signal).