Modulation of Reelin signaling by Cyclin-dependent kinase 5.
The Reelin signaling and Cyclin-dependent kinase 5 (Cdk5) both regulate neuronal positioning in the developing brain. Using double-transgenic mice, we have previously shown that these two signaling pathways lie in parallel fashion and have a genetic interaction. Disabled-1 (Dab1), an adapter protein, mediates Reelin signaling and becomes tyrosine-phosphorylated on the ... binding of Reelin to its receptors. Several isoforms of Dab1 are expressed in embryonic mouse brain, and p80 [Dab1(555)] is the major protein translated. In the present study, we investigated whether Cdk5-mediated phosphorylation of Dab1 modulates Reelin signaling. Cdk5 phosphorylates p80 Dab1 at multiple sites in its carboxyl-terminal region, and tyrosine phosphorylation of p80 Dab1 by Fyn tyrosine kinase is attenuated by this Cdk5-mediated phosphorylation in vitro. Tyrosine phosphorylation of p80 Dab1 induced by exogenous Reelin is enhanced in Cdk5-deficient neurons, corroborating the inhibitory effect of Cdk5-mediated Ser/Thr phosphorylation on tyrosine phosphorylation of p80 Dab1. Another isoform, p45 Dab1 [Dab1(271)], however, is phosphorylated by Cdk5 at one serine residue within a unique carboxyl-terminal region, and its serine phosphorylation enhances tyrosine phosphorylation by Fyn and results in progressive degradation of p45 Dab1. These results indicate that Cdk5 modulates Reelin signaling through the Ser/Thr phosphorylation of Dab1 differently in an isoform-specific manner.
Mesh Terms:
Animals, Cell Adhesion Molecules, Neuronal, Cells, Cultured, Cerebral Cortex, Chlorocebus aethiops, Cyclin-Dependent Kinase 5, Embryo, Mammalian, Extracellular Matrix Proteins, Female, Humans, Immunoprecipitation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Weight, Mutagenesis, Nerve Tissue Proteins, Neurons, Phosphorylation, Serine, Serine Endopeptidases, Signal Transduction, Threonine, Transfection
Animals, Cell Adhesion Molecules, Neuronal, Cells, Cultured, Cerebral Cortex, Chlorocebus aethiops, Cyclin-Dependent Kinase 5, Embryo, Mammalian, Extracellular Matrix Proteins, Female, Humans, Immunoprecipitation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Weight, Mutagenesis, Nerve Tissue Proteins, Neurons, Phosphorylation, Serine, Serine Endopeptidases, Signal Transduction, Threonine, Transfection
Brain Res
Date: Apr. 06, 2007
PubMed ID: 16529723
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