Nature 372, 794 - 798 (29 December 2002); doi:10.1038/372794a0

Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun

Irma Sánchez^*, Rowland T. Hughes^†, Bruce J. Mayer^‡§, Karen  Yee^†, James R. Woodgett, Joseph Avruch^*, John M. Kyriakls^* & Leonard I. Zon^†§£

^*Diabetes Research Laboratory, Medical Services, Massachusetts General Hospital East, and Department of Medicine Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
^†Division of Hematology/Oncology, ^‡Department of Microbiology and Molecular Genetics,
^§Howard Hughes Medical Institute, Children's Hospital and ¶ Dana-Farber Cancer Institute, Harvard Medical School, 300 Longwood Avenue, Enders 650, Boston, Massachusetts 02115, USA
Ontario Cancer Institute, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario M4X 1K9, Canada
^£To whom correspondence should be addressed.

THE stress-activated protein kinases (SAPKs), which are distantly related to the MAP kinases, are the dominant c-Jun amino-termi-nal protein kinases activated in response to a variety of cellular stresses, including treatment with tumour-necrosis factor- and interleukin- (refs 1, 2). SAPK phosphorylation of c-Jun probably activates the c-Jun transactivation function³. SAPKs are part of a signal transduction cascade related to, but distinct from, the MAPK pathway¹. We have now identified a novel protein kinase, called SAPK/ERK kinase-1 (SEK1), which is structurally related to the MAP kinase kinases (MEKs)⁴. SEK1 is a potent activator of the SAPKs in vitro and in vivo. An inactive SEK1 mutant blocks SAPK activation by extracellular stimuli without interfering with the MAPK pathway. Although alternative mechanisms of SAPK activation may exist, as an immediate upstream activator of the SAPKs, SEK1 further defines a signalling cascade that couples cellular stress agonists to the c-Jun transcription factor.