title: Semaphorin3A-induced axonal transport mediated through phosphorylation of Axin-1 by GSK3β.
abstract: The establishment of neuronal polarity is necessary for proper neuronal wiring. Semaphorin3A (Sema3A), originally identified as a repulsive axon guidance molecule, exerts a wide variety of biological functions through signaling pathways including sequential phosphorylation of collapsin response mediator protein by cyclin-dependent kinase-5 (Cdk5) and glycogen synthase kinase-3β (GSK3β). Sema3A acts on its receptor neuropilin-1 to regulate axonal transport. To delineate mechanism by which Sema3A induces axonal transport, we investigate whether GSK3β is involved in mediating Sema3A-induced axonal transport. 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione, an inhibitor of GSK3β, suppressed Sema3A-induced antero- and retrograde axonal transport. Introduction of either GSK3β mutants, GSK3β-L128A or K85M, suppressed Sema3A-induced axonal transport. On the other hand, introduction of GSK3β-R96A did not affect the Sema3A effect, suggesting that unprimed substrates are primarily involved in Sema3A-induced axonal transport. Overexpression of a partial fragment of frequently rearranged in advanced T-cell lymphomas 1 (FRATtide), which interferes the interaction between GSK3β and Axis inhibitor-1 (Axin-1), also suppressed Sema3A-induced transport. siRNA knockdown of Axin-1, an unprimed substrate of GSK3β, suppressed Sema3A-induced antero- and retrograde axonal transport. These results indicate that GSK3β and Axin-1 are involved in Sema3A-induced bidirectional axonal transport. This finding should provide a clue for understanding of mechanisms of a wide variety of biological activities of Sema3A.
authors.affiliation: Departments of Molecular Pharmacology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hida
authors.affiliation: Departments of Molecular Pharmacology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakamura
authors.affiliation: Departments of Molecular Pharmacology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Usui
authors.affiliation: Departments of Molecular Pharmacology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Departments of Molecular Pharmacology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Departments of Molecular Pharmacology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: goshima@med.yokohama-cu.ac.jp.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D040121:Semaphorin-3A / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D046509:Tissue Culture Techniques; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D030161:Avian Proteins; D060466:Axin Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D040121:Semaphorin-3A; D013830:Thiadiazoles; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Axin-1; Axon guidance; Axonal transport; Dorsal root ganglia; GSK3β; Semaphorin3a