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• W2012591441 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 (GADD45α/β/γ). 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." @default.
• W2012591441 created "2016-06-24" @default.
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• W2012591441 creator A5072313867 @default.
• W2012591441 creator A5075047745 @default.
• W2012591441 creator A5088224928 @default.
• W2012591441 date "2007-04-01" @default.
• W2012591441 modified "2023-10-10" @default.
• W2012591441 title "Activation of MTK1/MEKK4 by GADD45 through Induced N-C Dissociation and Dimerization-Mediated <i>trans</i> Autophosphorylation of the MTK1 Kinase Domain" @default.
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• W2012591441 doi "https://doi.org/10.1128/mcb.01435-06" @default.
• W2012591441 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1899887" @default.
• W2012591441 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17242196" @default.
• W2012591441 hasPublicationYear "2007" @default.
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