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Molecular and Cellular Biology, July 2002, p. 4544-4555, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4544-4555.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of MTK1/MEKK4 Kinase Activity by Its N-Terminal Autoinhibitory Domain and GADD45 Binding

Hiroaki Mita,1 Junichiro Tsutsui,1 Mutsuhiro Takekawa,2 Elizabeth A. Witten,1 and Haruo Saito1,2*

Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115,1 Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan2

Received 4 February 2002/ Returned for modification 18 March 2002/ Accepted 3 April 2002

A variety of cellular stresses activate the stress-responsive mitogen-activated protein (MAP) kinases p38 and JNK. In this study, we studied the activation mechanism of a human MAP kinase kinase kinase, MTK1 (also known as MEKK4), which mediates activation of both p38 and JNK. MTK1 has an extensive N-terminal noncatalytic domain composed of ~1,300 amino acids. Full-length or near full-length MTK1 is catalytically inactive when expressed in Saccharomyces cerevisiae cells, as it is in mammalian cells. Deletion of a segment including positions 253 to 553 activates kinase, indicating that this segment contains the autoinhibitory domain. In the autoinhibited conformation, the MTK1 kinase domain cannot interact with its substrate, MKK6. By a functional complementation screening with yeast cells, GADD45 proteins (GADD45{alpha}, ß, and {gamma}) were identified as MTK1 activators. GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition. Mutants of full-length MTK1 were isolated that can interact with MKK6 in the absence of the activator GADD45 proteins. These MTK1 mutants are constitutively active, in both yeast and mammalian cells. A model of MTK1 autoinhibition by the N-terminal inhibitory domain and activation by GADD45 binding is presented.

* Corresponding author. Mailing address: Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5505. Fax: 81-3-5449-5701. E-mail: h-saito{at}ims.u-tokyo.ac.jp.

Molecular and Cellular Biology, July 2002, p. 4544-4555, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4544-4555.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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