The p21-activated Kinase 3 Implicated in Mental Retardation Regulates Spine Morphogenesis through a Cdc42-dependent Pathway
| Autor: | Dominique Muller, Emmanuel Thévenot, Véronique Rousseau, Bernadette Boda, Jean-Vianney Barnier, Patricia Kreis |
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| Rok vydání: | 2007 |
| Předmět: |
rac1 GTP-Binding Protein
Dendritic spine Hippocampus/metabolism Synapses/metabolism Neurons/metabolism Dendritic spine morphogenesis Protein Serine-Threonine Kinases Biology Hippocampus Models Biological Synaptic Transmission Biochemistry Protein-Serine-Threonine Kinases/metabolism/ physiology Cdc42 GTP-Binding Protein/ metabolism Cercopithecus aethiops Rac1 GTP-Binding Protein/metabolism Mental Retardation/genetics/ metabolism Intellectual Disability Chlorocebus aethiops Animals Small GTPase Kinase activity cdc42 GTP-Binding Protein p21-activated kinases Molecular Biology Neurons Effector Cell Biology ddc:616.8 Rats Cell biology P21-Activated Kinases p21-Activated Kinases Cdc42 GTP-Binding Protein COS Cells Mutation Synapses Synaptic plasticity Cancer research |
| Zdroj: | Journal of Biological Chemistry, Vol. 282, No 29 (2007) pp. 21497-21506 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m703298200 |
| Popis: | The p21-activated kinase 3 (PAK3) is one of the recently identified genes for which mutations lead to nonsyndromic mental retardation. PAK3 is implicated in dendritic spine morphogenesis and is a key regulator of synaptic functions. However, the underlying roles of PAK3 in these processes remain poorly understood. We report here that the three mutations R419X, A365E, and R67C, responsible for mental retardation have different effects on the biological functions of PAK3. The R419X and A365E mutations completely abrogate the kinase activity. The R67C mutation drastically decreases the binding of PAK3 to the small GTPase Cdc42 and impairs its subsequent activation by this GTPase. We also report that PAK3 binds significantly more Cdc42 than Rac1 and is selectively activated by endogenous Cdc42, suggesting that PAK3 is a specific effector of Cdc42. Interestingly, the expression of the three mutated proteins in hippocampal neurons affects spinogenesis differentially. Both kinase-dead mutants slightly decrease the number of spines but profoundly alter spine morphology, whereas expression of the R67C mutant drastically decreases spine density. These results demonstrate that the Cdc42/PAK3 is a key module in dendritic spine formation and synaptic plasticity. |
| Databáze: | OpenAIRE |
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