Abstract
Mutations in doublecortin (DCX) cause X-linked lissencephaly ("smooth brain") and double cortex syndrome in humans. DCX is highly phosphorylated in migrating neurons. Here, we demonstrate that dephosphorylation of specific sites phosphorylated by JNK is mediated by Neurabin II, which recruits the phosphatase PP1. During cortical development, the expression pattern of PP1 is widespread, while the expression of DCX and Neurabin II is dynamic, and they are coexpressed in migrating neurons. In vitro, DCX is site-specific dephosphorylated by PP1 without the presence of Neurabin II, this dephosphorylation requires an intact RVXF motif in DCX. Overexpression of the coiled-coil domain of Neurabin II, which is sufficient for interacting with DCX and recruiting the endogenous Neurabin II with PP1, induced dephosphorylation of DCX on one of the JNK-phosphorylated sites. We hypothesize that the transient recruitment of DCX to different scaffold proteins, JIP-1/2, which will regulate its phosphorylation by JNK, and Neurabin II, which will regulate its dephosphorylation by PP1, plays an important role in normal neuronal migration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Motifs / physiology
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Animals
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Binding Sites / physiology
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Cell Differentiation / physiology
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Cell Line
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Cell Movement / physiology
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Cerebral Cortex / cytology
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Cerebral Cortex / embryology*
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Cerebral Cortex / metabolism*
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Doublecortin Domain Proteins
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Doublecortin Protein
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Gene Expression Regulation, Developmental / physiology
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Macromolecular Substances / metabolism
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Mice
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Mice, Inbred ICR
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Microfilament Proteins / chemistry
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Microfilament Proteins / metabolism*
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Microtubule-Associated Proteins / chemistry
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Microtubule-Associated Proteins / metabolism*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / metabolism*
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Nervous System Malformations / genetics
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Nervous System Malformations / metabolism
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Nervous System Malformations / physiopathology
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Neurons / cytology
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Neurons / metabolism*
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Neuropeptides / chemistry
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Neuropeptides / metabolism*
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation
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Protein Phosphatase 1
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Protein Structure, Tertiary / physiology
Substances
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Adaptor Proteins, Signal Transducing
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DCX protein, human
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Dcx protein, mouse
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Doublecortin Domain Proteins
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Doublecortin Protein
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Macromolecular Substances
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Mapk8ip protein, mouse
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Microfilament Proteins
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Neuropeptides
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neurabin
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JNK Mitogen-Activated Protein Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 1