Inactivation of mitogen-activated protein kinases by a mammalian tyrosine-specific phosphatase, PTPBR7

Mitogen-activated protein kinase (MAPK) is inactivated through dephosphoryl ation of tyrosyl and threonyl regulatory sites. In yeast, both dual-specifi city and tyrosine-specific phosphatases are involved in dephosphorylation. In mammals, however, no tyrosine-specific phosphatase has been identified m olecularly to dephosphorylate MAPK in vivo. Recently, we and others have cl oned a murine tyrosine-specific phosphatase, PTPBR7/PTP-SL, which is expres sed predominantly in the brain. Here we report inactivation of the extracel lular signal-regulated kinase (ERR) family MAPK by PTPBR7. PTPBR7 made comp lexes with ERK1/ERK2 in vivo and dephosphorylated ERK1 in vitro. When overe xpressed in mammalian cells, wild-type PTPBR7 suppressed the phosphorylatio n and activation of ERR by epidermal growth factor (EGF), nerve growth fact or (NGF), and constitutively active MEK1, a mutant MAPK kinase. In contrast , catalytically inactive and ERK-binding-deficient mutants revealed little inhibition on the ERK cascade. These results indicate that PTPBR7 suppresse s MAPK directly in vivo. (C) 1999 Academic Press.