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Molecular and Cellular Biology, April 2000, p. 2556-2568, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mixed-Lineage Kinase 3 Delivers CD3/CD28-Derived Signals into the Ikappa B Kinase Complex

Steffen P. Hehner,1 Thomas G. Hofmann,1 Alexej Ushmorov,1 Oliver Dienz,1 Irene Wing-Lan Leung,2 Norman Lassam,2 Claus Scheidereit,3 Wulf Dröge,1 and M. Lienhard Schmitz1,*

Department of Immunochemistry, German Cancer Research Center, 69120 Heidelberg,1 and Max Delbrück Center for Molecular Medicine, 13122 Berlin,3 Germany, and Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada2

Received 7 September 1999/Returned for modification 13 October 1999/Accepted 7 December 1999

The phosphorylation of Ikappa B by the multiprotein Ikappa B kinase complex (IKC) precedes the activation of transcription factor NF-kappa B, a key regulator of the inflammatory response. Here we identified the mixed-lineage group kinase 3 (MLK3) as an activator of NF-kappa B. Expression of the wild-type form of this mitogen-activated protein kinase kinase kinase (MAPKKK) induced nuclear immigration, DNA binding, and transcriptional activity of NF-kappa B. MLK3 directly phosphorylated and thus activated Ikappa B kinase alpha (IKKalpha ) and IKKbeta , revealing its function as an Ikappa B kinase kinase (IKKK). MLK3 cooperated with the other two IKKKs, MEKK1 and NF-kappa B-inducing kinase, in the induction of IKK activity. MLK3 bound to components of the IKC in vivo. This protein-protein interaction was dependent on the central leucine zipper region of MLK3. A kinase-deficient version of MLK3 strongly impaired NF-kappa B-dependent transcription induced by T-cell costimulation but not in response to tumor necrosis factor alpha or interleukin-1. Accordingly, endogenous MLK3 was phosphorylated and activated by T-cell costimulation but not by treatment of cells with tumor necrosis factor alpha or interleukin-1. A dominant negative version of MLK3 inhibited NF-kappa B- and CD28RE/AP-dependent transcription elicited by the Rho family GTPases Rac and Cdc42, thereby providing a novel link between these GTPases and the IKC.

* Corresponding author. Mailing address: Department of Immunochemistry, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-423725. Fax: 49-6221-423746. E-mail: L.Schmitz{at}DKFZ-Heidelberg.de.

Molecular and Cellular Biology, April 2000, p. 2556-2568, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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