Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling.
Plexins are neuronal receptors for the repulsive axon guidance molecule Semaphorins. Previous studies showed that Plexin B (PlexB) binds directly to the active, GTP-bound form of the Rac GTPase. Here, we define a seven amino acid sequence in PlexB required for Rac(GTP) binding. The interaction of PlexB with Rac(GTP) is necessary for Plexin-mediated axon guidance in vivo. A different region of PlexB binds to RhoA. Dosage-sensitive genetic interactions suggest that PlexB suppresses Rac activity and enhances RhoA activity. Biochemical evidence indicates that PlexB sequesters Rac(GTP) from its downstream effector PAK. These results suggest a model whereby PlexB mediates repulsion by coordinately regulating two small GTPases in opposite directions: PlexB binds to Rac(GTP) and downregulates its output by blocking its access to PAK and, at the same time, binds to and increases the output of RhoA.
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Howard Hughes Medical Institute, Division of Neurobiology, Department of Molecular and Cell Biology, 519 LSA, University of California, Berkeley, CA 94720, USA.
Marton
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Goodman
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D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000201:enzymology*; D001665:Binding Sites / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D016384:Consensus Sequence; D004330:Drosophila; D029721:Drosophila Proteins; D015870:Gene Expression / Q000502:physiology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D039961:Semaphorins; D015398:Signal Transduction / Q000502:physiology*; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D039961:Semaphorins; C116484:plexB protein, Drosophila; C099277:Pak protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein