Glucagon-induced expression of the MAP kinase phosphatase MKP-1 in rat hepatocytes

BACKGROUND & AIMS: Glucagon exerts pleiotropic effects on liver function, but the underlying signal transduction is incompletely understood. We investigated the effect of glucagon on the mitogen-activated protein (MAP) kinase phosphatase MKP-1 expression. METHODS: The effect of glucagon on MKP-1 expression was studied in cultured rat hepatocytes. RESULTS: Glucagon (10-100 nmol/L) and 8-CPT-cAMP (10 or 50 micromol/L) stimulated in rat hepatocytes the expression of MKP-1 messenger RNA and protein, which became maximal within 30 minutes and declined to nearly basal levels after 60 minutes. MKP-1 induction by glucagon was sensitive to inhibition of adenylate cyclase and protein kinase A. The protein kinases G and C, Ca(2+), MAP kinases, reactive oxygen intermediates, and cellular dehydration were not involved in the glucagon-induced signaling to MKP-1. MKP-1 expression correlated with glucagon-induced antagonization of MAP kinase phosphorylation by epidermal growth factor in hepatocytes. CONCLUSIONS: The MKP-1 response to glucagon produces an additional level of interaction with MAP kinase-dependent processes, which may contribute to the regulation of liver function by glucagon or other cAMP-elevating agents.