Activation of Mtk1/Mekk4 by Gadd45 Through Induced N-c Dissociation and Dimerization-mediated Trans Autophosphorylation of the Mtk1 Kinase Domain.
From: Institute of Medical Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Molecular and cellular biology
- Publish Date: Apr 2007
- ISSN: 0270-7306
- Volume: 27
- Issue: 7
- Pages: 2765-76
- Medium: Print
- Language: English
- Citation (JAMA): Miyake Zenshi, Takekawa Mutsuhiro, Ge Qingyuan, et al. Activation of Mtk1/Mekk4 by Gadd45 Through Induced N-c Dissociation and Dimerization-mediated Trans Autophosphorylation of the Mtk1 Kinase Domain.. Mol. Cell. Biol. Apr 2007;27:2765-76
Abstract
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 (GADD45alpha/beta/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.
Mesh Headings (Keywords): Animals, COS Cells, Cercopithecus aethiops, Dimerization, Enzyme Activation, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase Kinase 4, Mutation, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Signal Transduction, Tyrosine
Check for Full Text / PubMed Unique Identifier (PMID): 17242196
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