Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase.
BACKGROUND
The p35-Cdk5 kinase has been implicated in a variety of functions in the central nervous system (CNS), including axon outgrowth, axon guidance, fasciculation, and neuronal migration during cortical development. In p35(-/-) mice, embryonic cortical neurons are unable to migrate past their predecessors, leading to an inversion of cortical layers in the adult cortex.


RESULTS
In order to identify molecules important for p35-Cdk5-dependent function in the cortex, we screened for p35-interacting proteins using the two-hybrid system. In this study, we report the identification of a novel interaction between p35 and the versatile cell adhesion signaling molecule beta-catenin. The p35 and beta-catenin proteins interacted in vitro and colocalized in transfected COS cells. In addition, the p35-Cdk5 kinase was associated with a beta-catenin-N-cadherin complex in the cortex. In N-cadherin-mediated aggregation assays, inhibition of Cdk5 kinase activity using the Cdk5 inhibitor roscovitine led to the formation of larger aggregates of embryonic cortical neurons. This finding was recapitulated in p35(-/-) cortical neurons, which aggregated to a greater degree than wild-type neurons. In addition, introduction of active p35-Cdk5 kinase into COS cells led to a decreased beta-catenin-N-cadherin interaction and loss of cell adhesion.


CONCLUSIONS
The association between p35-Cdk5 and an N-cadherin adhesion complex in cortical neurons and the modulation of N-cadherin-mediated aggregation by p35-Cdk5 suggests that the p35-Cdk5 kinase is involved in the regulation of N-cadherin-mediated adhesion in cortical neurons.
Kwon
Y T
YT
Health Advances, Inc., Wellesley, Massachusetts 02181, USA.
Gupta
A
A
Zhou
Y
Y
Nikolic
M
M
Tsai
L H
LH
D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002449:Cell Aggregation; D002465:Cell Movement; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators; D020798:Two-Hybrid System Techniques; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D002118:Calcium