BIG MITOGEN-ACTIVATED PROTEIN-KINASE-1 (BMK1) IS A REDOX-SENSITIVE KINASE

Mitogen-activated protein (MAP) kinases are a multigene family activat ed by many extracellular stimuli. There are three groups of MAP kinase s 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 famil y member termed Big MAP kinase 1 (BMK1) or ERK5 was recently cloned, B MK1 has a TEY sequence similar to ERK1/2 but has unique COOH-terminal and loop-12 domains, To define BMK1 regulation, its activation in cult ured rat vascular smooth muscle cells was characterized. Angiotensin I I, phorbol ester, platelet-derived growth factor, and tumor necrosis f actor-alpha were the strongest stimuli for ERK1/2 but were weak activa tors of BMK1. In contrast, H2O2 caused concentration-dependent activat ion of BMK1 but not ERK1/2. Sorbitol activated both BMK1 and ERK1/2. B MK1 activation by H2O2 was calcium-dependent and appeared ubiquitous a s shown by stimulation in human skin fibroblasts, human vascular smoot h muscle cells, and human umbilical vein endothelial cells, These find ings demonstrate that activation of BMK1 is different from ERK1/2 and suggest an important role for BMK1 as a redox-sensitive kinase.