This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Miyake, Z.
Right arrow Articles by Saito, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Miyake, Z.
Right arrow Articles by Saito, H.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Horie, T., Tatebayashi, K., Yamada, R., Saito, H. (2008). Phosphorylated Ssk1 Prevents Unphosphorylated Ssk1 from Activating the Ssk2 Mitogen-Activated Protein Kinase Kinase Kinase in the Yeast High-Osmolarity Glycerol Osmoregulatory Pathway. Mol. Cell. Biol. 28: 5172-5183 [Abstract] [Full Text]  
  • Jacamo, R., Sinnett-Smith, J., Rey, O., Waldron, R. T., Rozengurt, E. (2008). Sequential Protein Kinase C (PKC)-dependent and PKC-independent Protein Kinase D Catalytic Activation via Gq-coupled Receptors: DIFFERENTIAL REGULATION OF ACTIVATION LOOP SER744 AND SER748 PHOSPHORYLATION. J. Biol. Chem. 283: 12877-12887 [Abstract] [Full Text]  
  • Schrag, J. D., Jiralerspong, S., Banville, M., Jaramillo, M. L., O'Connor-McCourt, M. D. (2008). The crystal structure and dimerization interface of GADD45{gamma}. Proc. Natl. Acad. Sci. USA 105: 6566-6571 [Abstract] [Full Text]  
  • Murakami, Y., Tatebayashi, K., Saito, H. (2008). Two Adjacent Docking Sites in the Yeast Hog1 Mitogen-Activated Protein (MAP) Kinase Differentially Interact with the Pbs2 MAP Kinase Kinase and the Ptp2 Protein Tyrosine Phosphatase. Mol. Cell. Biol. 28: 2481-2494 [Abstract] [Full Text]  
  • Peretz, G., Bakhrat, A., Abdu, U. (2007). Expression of the Drosophila melanogaster GADD45 Homolog (CG11086) Affects Egg Asymmetric Development That Is Mediated by the c-Jun N-Terminal Kinase Pathway. Genetics 177: 1691-1702 [Abstract] [Full Text]  
  • Abell, A. N., Granger, D. A., Johnson, G. L. (2007). MEKK4 Stimulation of p38 and JNK Activity Is Negatively Regulated by GSK3beta. J. Biol. Chem. 282: 30476-30484 [Abstract] [Full Text]  
  • Mattison, C. P., Old, W. M., Steiner, E., Huneycutt, B. J., Resing, K. A., Ahn, N. G., Winey, M. (2007). Mps1 Activation Loop Autophosphorylation Enhances Kinase Activity. J. Biol. Chem. 282: 30553-30561 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»