Abstract
Secreted Semaphorin3A (Sema3A) proteins are known to act as diffusible and repellant axonal guidance cues during nervous system development. A receptor complex consisting of a Neuropilin and a Plexin-A mediates their effects. Plexin-A signal transduction has remained poorly defined despite the documented involvement of collapsin response mediator protein and molecule interacting with CasL proteins (MICALs) as mediators of Plexin-A activation. Here, we defined a domain of Plexin-A1 required for Sema3A signaling in a reconstituted environment and then searched for proteins interacting with this domain. RanBPM is shown to physically interact with Plexin-A1, and the RanBPM/Plexin complex is regulated by MICAL expression. Overexpression of RanBPM cooperates with PlexinA1 to reduce non-neuronal cell spreading and strongly inhibit axonal outgrowth in vitro and in vivo. A truncated RanBPM protein blocks Sema3A responsiveness in non-neuronal and neuronal cells. Suppression of RanBPM expression reduces Sema3A responsiveness. Thus, RanBPM is a mediator of Sema3A signaling through Plexin-A. RanBPM has the potential to link Plexin-A receptors to retrograde transport and microtubule function in axonal guidance.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Cell Adhesion Molecules / metabolism*
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Cell Death / drug effects
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Cell Death / physiology
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Cell Size
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Cells, Cultured
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Chick Embryo
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Cloning, Molecular / methods
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Cricetinae
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Cricetulus
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Cytoskeletal Proteins
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Dose-Response Relationship, Drug
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Drug Interactions
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Enzyme Inhibitors / pharmacology
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Ganglia, Spinal / cytology
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Gene Expression / drug effects
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Green Fluorescent Proteins / metabolism
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Humans
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Immunoprecipitation / methods
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In Situ Nick-End Labeling / methods
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Nerve Tissue Proteins / metabolism*
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Neurites / physiology
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Neurons / cytology
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Neurons / drug effects
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Neurons / physiology*
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Neuropilin-1 / metabolism
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Nuclear Proteins / physiology*
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Semaphorin-3A / metabolism*
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Semaphorin-3A / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transcription Factor AP-1 / pharmacology
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Transfection / methods
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Two-Hybrid System Techniques
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ran GTP-Binding Protein / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Cell Adhesion Molecules
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Nerve Tissue Proteins
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Nuclear Proteins
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Ran binding protein 9
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Semaphorin-3A
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Transcription Factor AP-1
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plexin
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Neuropilin-1
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Green Fluorescent Proteins
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ran GTP-Binding Protein