Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1

Abstract

A KINASE distinct from the MEK activator Raf1-3, termed MEK kinase-1 (MEKK), was originally identified by virtue of its homo-logy to kinases involved in yeast mating signal cascades4. Like Raf, MEKK is capable of activating MEK in vitro4,5. High-level expression of MEKK in COS-7 cells4 or using vaccinia virus vectors5 also activates MEK and MAPK, indicating that MEKK and Raf provide alternative means of activating the MAPK signal-ling pathway. We have derived NIH3T3 cell sublines that can be induced to express active MEKK. Here we show that induction of MEKK does not result in the activation of MAPK, but instead stimulates the stress-activated protein kinases (SAPKs)6-8 which are identical to a Jun amino-terminal kinase9,10. We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK. © 2002 Nature Publishing Group.