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Sci. STKE, 9 December 2003
Vol. 2003, Issue 212, p. tw477
[DOI: 10.1126/stke.2122003TW477]

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NEURONAL MIGRATION Dab1 Degradation Limits Reelin Signaling

The laminar structure of the mammalian brain arises through the migration of neurons to distinct locations during development. Binding of the secreted glycoprotein Reelin to either the very low density lipoprotein receptor or the ApoE receptor 2 present on specific neurons results in the tyrosine phosphorylation of a cytoplasmic protein called Dab1. This event initiates a signaling cascade that is believed to stop neuronal migration. However, Arnaud et al. have identified how this Reelin signaling pathway is down-regulated in cortical neurons isolated from mouse embryos. The half-life of Dab1 was determined to be about 12 hours, but treatment of neurons with Reelin reduced this to about 3 hours. Reelin stimulated rapid tyrosine phosphorylation of a subpopulation of Dab1. Furthermore, serine-threonine phosphorylation of Dab1 appeared to be necessary for subsequent phosphorylation on tyrosine. These modifications marked Dab1 for polyubiquitination, and Dab1 degradation was blocked in the presence of protease inhibitors, which implicated the ubiquitin-proteasome pathway. A mutant form of Dab1 that cannot be tyrosine phosphorylated was protected from degradation upon Reelin stimulation. It is not yet clear how Dab1 is recognized by the ubiquitination machinery. This mechanism of down-regulation may limit the duration of the Reelin signal in neurons.

L. Arnaud, B. A. Balif, J. A. Cooper, Regulation of protein tyrosine kinase signaling by substrate degradation during brain development. Mol. Cell. Biol. 23, 9293-9302 (2003). [Abstract] [Full Text]

Citation: Dab1 Degradation Limits Reelin Signaling. Sci. STKE 2003, tw477 (2003).



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