INDUCTION OF MITOGEN-ACTIVATED PROTEIN-KINASE PHOSPHATASE-1 BY THE STRESS-ACTIVATED PROTEIN-KINASE SIGNALING PATHWAY BUT NOT BY EXTRACELLULAR SIGNAL-REGULATED KINASE IN FIBROBLASTS

The intracellular mechanisms involved in the activation of extracellul ar signal-regulated kinase (ERK) are relatively well understood. Howev er, the intracellular signaling pathways which regulate the terminatio n of ERK activity remain to be elucidated. Mitogen-activated protein k inase phosphatase 1 (MKP-1) has been shown to dephosphorylate and inac tivate ERK in vitro and in vivo. In the present study, we show in NIH3 T3 fibroblasts that activation of the stress-activated protein kinase (SAPK) pathway by either specific extracellular stress stimuli or via induction of MEKK, an upstream kinase of SAPK, results in MKP-1 gene e xpression, In contrast, selective stimulation of the ERK pathway by 12 -O-tetradecanoylphorbol-13-acetate or following expression of constitu tively active MEK, the upstream dual specificity kinase of ERK did not induce the transcription of MKP-1, Hence, these findings demonstrate the existence of cross-talk between the ERK and SAPK signaling cascade s since activation of SAPK induced the expression of MKP-1 that can in activate ERK, This mechanism may modulate the cellular response to sti muli which employ the SAPK signal transduction pathway.