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Molecular and Cellular Biology, April 2007, p. 2765-2776, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01435-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activation of MTK1/MEKK4 by GADD45 through Induced N-C Dissociation and Dimerization-Mediated trans Autophosphorylation of the MTK1 Kinase Domain{triangledown} ,{dagger}

Zenshi Miyake,1,2,{ddagger} Mutsuhiro Takekawa,1,2,{ddagger}* Qingyuan Ge,3 and Haruo Saito1,2*

Division of Molecular Cell Signaling, Institute of Medical Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,1 Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,2 Cell Signaling Technology, Inc., 3 Trask Lane, Danvers, Massachusetts 019233

Received 4 August 2006/ Returned for modification 3 October 2006/ Accepted 9 January 2007

The mitogen-activated protein kinase (MAPK) module, composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK), is a cellular signaling device that is conserved throughout the eukaryotic world. In mammalian cells, various extracellular stresses activate two major subfamilies of MAPKs, namely, the Jun N-terminal kinases and the p38/stress-activated MAPK (SAPK). MTK1 (also called MEKK4) is a stress-responsive MAPKKK that is bound to and activated by the stress-inducible GADD45 family of proteins (GADD45{alpha}/ß/{gamma}). Here, we dissected the molecular mechanism of MTK1 activation by GADD45 proteins. The MTK1 N terminus bound to its C-terminal segment, thereby inhibiting the C-terminal kinase domain. This N-C interaction was disrupted by the binding of GADD45 to the MTK1 N-terminal GADD45-binding site. GADD45 binding also induced MTK1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of MTK1 at Thr-1493 in the kinase activation loop. An MTK1 alanine substitution mutant at Thr-1493 has a severely reduced activity. Thus, we conclude that GADD45 binding induces MTK1 N-C dissociation, dimerization, and autophosphorylation at Thr-1493, leading to the activation of the kinase catalytic domain. Constitutively active MTK1 mutants induced the same events, but in the absence of GADD45.

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

{triangledown} Published ahead of print on 22 January 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, April 2007, p. 2765-2776, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01435-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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