Site-specific dephosphorylation of doublecortin (DCX) by protein phosphatase 1 (PP1).
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.
Shmueli
Anat
A
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Gdalyahu
Amos
A
Sapoznik
Sivan
S
Sapir
Tamar
T
Tsukada
Miki
M
Reiner
Orly
O
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary / Q000502:physiology; D000099273:Neurabins
D048868:Adaptor Proteins, Signal Transducing; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D048031:JNK Mitogen-Activated Protein Kinases; D046911:Macromolecular Substances; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D000099273:Neurabins; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; C490665:Mapk8ip protein, mouse