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Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2005 Dec 30; Vol. 280 (52), pp. 42984-93. Date of Electronic Publication: 2005 Oct 27. - Publication Year :
- 2005
-
Abstract
- Mixed lineage kinase 3 (MLK3) functions as a mitogen-activated protein kinase kinase kinase to activate multiple mitogen-activated protein kinase pathways. Our current studies demonstrate that lack of MLK3 blocks signaling of activated Cdc42 to c-Jun N-terminal kinase, giving strong support for the idea that Cdc42 is a physiological activator of MLK3. We show herein that Cdc42, in a prenylation-dependent manner, targets MLK3 from a perinuclear region to membranes, including the plasma membrane. Cdc42-induced membrane targeting of MLK3 is independent of MLK3 catalytic activity but depends upon an intact Cdc42/Rac-interactive binding motif, consistent with MLK3 membrane translocation being mediated through direct binding of Cdc42. Phosphorylation of the activation loop of MLK3 requires MLK3 catalytic activity and is induced by Cdc42 in a prenylation-independent manner, arguing that Cdc42 binding is sufficient for activation loop autophosphorylation of MLK3. However, membrane targeting is necessary for full activation of MLK3 and maximal signaling to JNK. We previously reported that MLK3 is autoinhibited through an interaction between its N-terminal SH3 domain and a proline-containing sequence found between the leucine zipper and the CRIB motif of MLK3. Thus we propose a model in which GTP-bound Cdc42/Rac binds MLK3 and disrupts SH3-mediated autoinhibition leading to dimerization and activation loop autophosphorylation. Targeting of this partially active MLK3 to membranes likely results in additional phosphorylation events that fully activate MLK3 and its ability to maximally signal through the JNK pathway.
- Subjects :
- Amino Acid Motifs
Amino Acid Sequence
Blotting, Western
Catalysis
DNA, Complementary metabolism
Dimerization
Electrophoresis, Polyacrylamide Gel
Enzyme Activation
Genetic Vectors
HeLa Cells
Humans
JNK Mitogen-Activated Protein Kinases chemistry
MAP Kinase Kinase 4 metabolism
MAP Kinase Signaling System
Microscopy, Confocal
Microscopy, Fluorescence
Microscopy, Phase-Contrast
Molecular Sequence Data
Mutagenesis, Site-Directed
Phosphorylation
Proline chemistry
Protein Structure, Tertiary
Signal Transduction
Subcellular Fractions metabolism
Transfection
cdc42 GTP-Binding Protein metabolism
Mitogen-Activated Protein Kinase Kinase Kinase 11
Cell Membrane metabolism
Gene Expression Regulation, Enzymologic
MAP Kinase Kinase Kinases chemistry
cdc42 GTP-Binding Protein physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 52
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16253996
- Full Text :
- https://doi.org/10.1074/jbc.M502671200