Role of MAP kinase phosphatases in GnRH-dependent activation of MAP kinases

GnRH controls the synthesis and release of the pituitary gonadotropic hormones. MAP kinase (MAPK) cascades, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways, are crucial for GnRH-induced gene activation. In the present study, we investigated the function of GnRH-induced MAPK phosphatases (MKPs) using an in vivo mouse model as well as the alpha T3-1 cell line. Following GnRH agonist stimulation, in vivo gene profiling demonstrated that both MKP-1 and MKP-2 are induced with distinct temporal profiles, suggesting differential roles of these MKPs in the regulation of MAPK activation. Elevated activity of MKP-2 in alpha T3-1 cells, through either overexpression or activation of the endogenous MKP-2 gene, was correlated with inhibition of GnRH-induced activation of ERK and JNK, as well as the expression of ERK- and JNK-dependent proto-oncogenes. These data supported the conclusion that GnRH-induced MKPs likely serve as negative feedback regulators that modulate MAPK activity and function in the GnRH signaling pathway.