title: Phosphorylation of drebrin by cyclin-dependent kinase 5 and its role in neuronal migration.
abstract: Cyclin-dependent kinase 5 (Cdk5)-p35 is a proline-directed Ser/Thr kinase which plays a key role in neuronal migration, neurite outgrowth, and spine formation during brain development. Dynamic remodeling of cytoskeletons is required for all of these processes. Cdk5-p35 phosphorylates many cytoskeletal proteins, but it is not fully understood how Cdk5-p35 regulates cytoskeletal reorganization associated with neuronal migration. Since actin filaments are critical for the neuronal movement and process formation, we aimed to find Cdk5 substrates among actin-binding proteins. In this study, we isolated actin gels from mouse brain extracts, which contain many actin-binding proteins, and phosphorylated them by Cdk5-p35 in vitro. Drebrin, a side binding protein of actin filaments and well known for spine formation, was identified as a phosphorylated protein. Drebrin has two isoforms, an embryonic form drebrin E and an adult type long isoform drebrin A. Ser142 was identified as a common phosphorylation site to drebrin E and A and Ser342 as a drebrin A-specific site. Phosphorylated drebrin is localized at the distal area of total drebrin in the growth cone of cultured primary neurons. By expressing nonphosphorylatable or phosphorylation mimicking mutants in developing neurons in utero, the reversible phosphorylation/dephosphorylation reaction of drebrin was shown to be involved in radial migration of cortical neurons. These results suggest that Cdk5-p35 regulates neuronal migration through phosphorylation of drebrin in growth cone processes.
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Molecular Neurobiology, Institute for Developmental Research, Kasugai, Aichi, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inaguma
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Asada
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Takahashi
authors.affiliation: Department of Chemistry, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Taoka
authors.affiliation: Department of Life Science and Medical Bio-Science, Waseda University, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
authors.affiliation: Department of Chemistry, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Molecular Neurobiology, Institute for Developmental Research, Kasugai, Aichi, Japan.
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Shirao
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005782:Gels; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000201:enzymology*; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D021381:Protein Transport; D013379:Substrate Specificity
chemical_list: C492236:Cdk5r1 protein, mouse; D005782:Gels; D050505:Mutant Proteins; D009479:Neuropeptides; C053386:drebrins; D010768:Phosphoserine; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5