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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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