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The Journal of Neuroscience, September 15, 2002, 22(18):7948-7958

A New Activity of Doublecortin in Recognition of the Phospho-FIGQY Tyrosine in the Cytoplasmic Domain of Neurofascin

Krishnakumar Kizhatil, Yi-Xin Wu, Anindita Sen, and Vann Bennett

Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neuroscience, Duke University Medical Center, Durham, North Carolina 27710

Doublecortin is a cytoplasmic protein mutated in the neuronal migration disorder X-linked lissencephaly. This study describes a novel activity of doublecortin in recognition of the FIGQY-phosphotyrosine motif present in the cytoplasmic domain of the L1 cell adhesion molecule neurofascin. Phospho-FIGQY-neurofascin (186 kDa) coimmunoprecipitated with doublecortin from detergent extracts of embryonic brain membranes, and this doublecortin-phospho-FIGQY neurofascin complex was disassociated by a synthetic phospho-FIGQY neurofascin peptide but not by a dephospho-FIGQY peptide. Doublecortin specifically recognized the phospho-FIGQY tyrosine in the context of a synthetic phospho-FIGQY neurofascin peptide and in phospho-FIGQY neurofascin isolated from cells treated with pervanadate. Mutations of doublecortin causing lissencephaly (R59H, D62N, and G253D) abolished binding to the phospho-FIGQY peptide and to phospho-FIGQY neurofascin. Finally, phospho-FIGQY neurofascin and doublecortin colocalize in developing axon tracts and in zones enriched in migrating neurons in the embryonic cerebral cortex. In the adult rostral migratory stream, doublecortin colocalizes in migrating neurons with a phospho-FIGQY bearing L1 CAM different from neurofascin. The finding that doublecortin associates with FIGQY-phosphorylated neurofascin provides the first connection of doublecortin with the plasma membrane and could be important for a function of doublecortin in directing neuronal migration.

Key words: doublecortin; phospho-FIGQY; neurofascin; L1 CAM; neuronal migration; axons


Copyright © 2002 Society for Neuroscience  0270-6474/02/22187948-11$05.00/0


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