Activation of the IκBα Kinase Complex by MEKK1, a Kinase of the JNK Pathway

• Published in: Cell 1997-01, Vol.88 (2), p.213-222
• Main Authors: Lee, Frank S, Hagler, Jeremiah, Chen, Zhijian J, Maniatis, Tom
• Format: Article
• Language: English
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)81842-5

Both NF-κB and c-Jun are activated by cytokines such as TNF-α and by stresses such as UV irradiation. A key step in the activation of NF-κB is the phosphorylation of its inhibitor, IκBα, by a ubiquitination-inducible multiprotein kinase complex (IκBα kinase). A central kinase in the c-Jun activation pathway is mito- gen-activated protein kinase/ERK kinase kinase-1 (MEKK1). Here, we show that MEKK1 induces the site-specific phosphorylation of IκBα in vivo and, most strikingly, can directly activate the IκBα kinase complex in vitro. Thus, MEKK1 is a critical component of both the c-Jun and NF-κB stress response pathways. Since the IκBα kinase complex can be independently activated by ubiquitination or MEKK1-dependent phosphorylation, it may be an integrator of multiple signal transduction pathways leading to the activation of NF-κB.