Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration.
The serine/threonine kinase Cdk5 plays an essential role in neuronal positioning during corticogenesis, but the underlying mechanisms are unknown. In nonneuronal cells, the tyrosine kinase FAK is a major regulator of cell motility through focal adhesions. It is unclear whether FAK plays a role in brain development. Here, we show that FAK phosphorylation by Cdk5 at S732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, S732-phosphorylated FAK is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant FAK S732A results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo. These observations are reminiscent of what is seen in the Cdk5-deficient mice. Taken together, these results suggest that Cdk5 phosphorylation of FAK is critical for neuronal migration through regulation of a microtubule fork important for nuclear translocation.
Xie
Zhigang
Z
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Sanada
Kamon
K
Samuels
Benjamin Adam
BA
Shih
Heather
H
Tsai
Li Huei
LH
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D002540:Cerebral Cortex / Q000196:embryology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D018274:Electroporation / Q000379:methods; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D014404:Tubulin; D012694:Serine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases