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

Dirk Bokemeyer,Andrey Sorokin,Minhong Yan,Natalie G Ahn,Dennis J Templeton,Michael J Dunn

doi:10.1074/jbc.271.2.639

Abstract

The intracellular mechanisms involved in the activation of extracellular signal-regulated kinase (ERK) are relatively well understood. However, the intracellular signaling pathways which regulate the termination of ERK activity remain to be elucidated. Mitogen-activated protein kinase phosphatase 1 (MKP-1) has been shown to dephosphorylate and inactivate ERK in vitro and in vivo. In the present study, we show in NIH3T3 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 expression. In contrast, selective stimulation of the ERK pathway by 12-O-tetradecanoylphorbol-13-acetate or following expression of constitutively 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 cascades since activation of SAPK induced the expression of MKP-1 that can inactivate ERK. This mechanism may modulate the cellular response to stimuli which employ the SAPK signal transduction pathway.

Highlights

The intracellular mechanisms involved in the activation of extracellular signal-regulated kinase (ERK) are relatively well understood
These findings demonstrate the existence of cross-talk between the Extracellular signalregulated kinase (ERK) and stress-activated protein kinase (SAPK) signaling cascades since activation of SAPK induced the expression of Mitogen-activated protein kinase phosphatase 1 (MKP-1) that can inactivate ERK
One is the intensively investigated Raf-MEK-ERK cascade and the other recently described kinase cascade is initiated by MEKK (MEK kinase) leading to activation of SEK1, the upstream dual specificity kinase of stress-activated protein kinase (SAPK), that in turn phosphorylates and activates SAPK

Summary

Introduction

The intracellular mechanisms involved in the activation of extracellular signal-regulated kinase (ERK) are relatively well understood. We demonstrate the induction of MKP-1 in response to activation of the SAPK signaling pathway but not after stimulation of ERK. Parental NIH3T3 cells with serum, MKP-1 expression was induced rapidly (Fig. 1A).

Results

Conclusion