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Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology.

The small GTPase Rac and its effectors, the Pak1 and p35/Cdk5 kinases, have been assigned important roles in regulating cytoskeletal dynamics in neurons. Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase. In neuronal growth cones, Pak1 phosphorylated on Thr-212 localized to actin and tubulin-rich areas, suggesting a role in regulating growth cone dynamics. The expression of a non-phosphorylatable Pak1 mutant (Pak1A212) induced dramatic neurite disorganization. We also observed a strong association between p35/Cdk5 and the Pak1 C-terminal kinase domain. Overall, our data show that in neurons, membrane-associated, active Pak1 is regulated by the p35/Cdk5 kinase both by association and phosphorylation, which is essential for the proper regulation of the cytoskeleton during neurite outgrowth and remodeling.

Pubmed ID: 11604394 RIS Download

Mesh terms: Animals | Cell Size | Cells, Cultured | Cerebral Cortex | Cyclin-Dependent Kinase 5 | Cyclin-Dependent Kinases | Cytoskeleton | Growth Cones | Immunohistochemistry | Mice | Models, Biological | Neurons | Phosphorylation | Protein Structure, Tertiary | Protein-Serine-Threonine Kinases | Rats | Recombinant Fusion Proteins | p21-Activated Kinases | rac GTP-Binding Proteins

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