Conserved Docking Site Is Essential for Activation of Mammalian MAP Kinase Kinases by Specific MAP Kinase Kinase Kinases

Mammalian mitogen-activated protein kinase (MAPK) cascades control various cellular events, ranging from cell growth to apoptosis, in response to external stimuli. A conserved docking site, termed DVD, is found in the mammalian MAP kinase kinases (MAPKKs) belonging to the three major subfamilies, na...

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Bibliographic Details
Published in:Molecular cell 2005-04, Vol.18 (3), p.295-306
Main Authors: Takekawa, Mutsuhiro, Tatebayashi, Kazuo, Saito, Haruo
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding Sites
Cell Line
Enzyme Activation
Humans
MAP Kinase Kinase Kinases - genetics
MAP Kinase Kinase Kinases - metabolism
MAP Kinase Signaling System - physiology
Mitogen-Activated Protein Kinase Kinases - chemistry
Mitogen-Activated Protein Kinase Kinases - genetics
Mitogen-Activated Protein Kinase Kinases - metabolism
Molecular Sequence Data
Peptides - genetics
Peptides - metabolism
Protein Binding
Protein Folding
Sequence Alignment
Two-Hybrid System Techniques
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Summary:Mammalian mitogen-activated protein kinase (MAPK) cascades control various cellular events, ranging from cell growth to apoptosis, in response to external stimuli. A conserved docking site, termed DVD, is found in the mammalian MAP kinase kinases (MAPKKs) belonging to the three major subfamilies, namely MEK1, MKK4/7, and MKK3/6. The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAPKKKs), including MTK1 (MEKK4), ASK1, TAK1, TAO2, MEKK1, and Raf-1. DVD site is a stretch of about 20 amino acids immediately on the C-terminal side of the MAPKK catalytic domain. Mutations in the DVD site strongly inhibited MAPKKs from binding to, and being activated by, their specific MAPKKKs, both in vitro and in vivo. DVD site mutants could not be activated by various external stimuli in vivo. Synthetic DVD oligopeptides inhibited specific MAPKK activation, both in vitro and in vivo, demonstrating the critical importance of the DVD docking in MAPK signaling.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2005.04.001