Big Mitogen-activated Protein Kinase 1 (BMK1) Is a Redox-sensitive Kinase

Jun-Ichi Abe,Masatoshi Kusuhara,Richard J Ulevitch,Bradford C Berk,Jiing-Dwan Lee

doi:10.1074/jbc.271.28.16586

Abstract

Mitogen-activated protein (MAP) kinases are a multigene family activated by many extracellular stimuli. There are three groups of MAP kinases based on their dual phosphorylation motifs, TEY, TPY, and TGY, which are termed extracellular signal-regulated protein kinases (ERK1/2), c-Jun N-terminal kinases, and p38, respectively. A new MAP kinase family member termed Big MAP kinase 1 (BMK1) or ERK5 was recently cloned. BMK1 has a TEY sequence similar to ERK1/2 but has unique COOH-terminal and loop-12 domains. To define BMK1 regulation, its activation in cultured rat vascular smooth muscle cells was characterized. Angiotensin II, phorbol ester, platelet-derived growth factor, and tumor necrosis factor-alpha were the strongest stimuli for ERK1/2 but were weak activators of BMK1. In contrast, H2O2 caused concentration-dependent activation of BMK1 but not ERK1/2. Sorbitol activated both BMK1 and ERK1/2. BMK1 activation by H2O2 was calcium-dependent and appeared ubiquitous as shown by stimulation in human skin fibroblasts, human vascular smooth muscle cells, and human umbilical vein endothelial cells. These findings demonstrate that activation of BMK1 is different from ERK1/2 and suggest an important role for BMK1 as a redox-sensitive kinase.

Highlights

The mitogen-activated protein (MAP)1,2 kinase cascade is a major signaling system by which cells transduce extracellular stimuli into intracellular responses [1]
We have previously shown that these agonists are potent stimuli for activation of ERK1/2 [12, 13], which contain a the same dual phosphorylation site (TEY) dual phosphorylation site identical to that present in Big MAP kinase 1 (BMK1)
The results presented below indicate that activation of BMK1 by these agonists is very different from activation of ERK1/2

Summary

Introduction

The mitogen-activated protein (MAP)1,2 kinase cascade is a major signaling system by which cells transduce extracellular stimuli into intracellular responses [1]. To define the regulation of BMK1, we have characterized its activation in cultured rat VSMC, which we have previously shown to have robust ERK activity in response to several stimuli. We have previously shown that these agonists are potent stimuli for activation of ERK1/2 [12, 13], which contain a TEY dual phosphorylation site identical to that present in BMK1.

Results

Conclusion