title: 14-3-3ε couples protein kinase A to semaphorin signaling and silences plexin RasGAP-mediated axonal repulsion.
abstract: The biochemical means through which multiple signaling pathways are integrated in navigating axons is poorly understood. Semaphorins are among the largest families of axon guidance cues and utilize Plexin (Plex) receptors to exert repulsive effects on axon extension. However, Semaphorin repulsion can be silenced by other distinct cues and signaling cascades, raising questions of the logic underlying these events. We now uncover a simple biochemical switch that controls Semaphorin/Plexin repulsive guidance. Plexins are Ras/Rap family GTPase activating proteins (GAPs) and we find that the PlexA GAP domain is phosphorylated by the cAMP-dependent protein kinase (PKA). This PlexA phosphorylation generates a specific binding site for 14-3-3ε, a phospho-binding protein that we find to be necessary for axon guidance. These PKA-mediated Plexin-14-3-3ε interactions prevent PlexA from interacting with its Ras family GTPase substrate and antagonize Semaphorin repulsion. Our results indicate that these interactions switch repulsion to adhesion and identify a point of convergence for multiple guidance molecules.
authors.affiliation: Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Taehong
authors.initials: T
authors.lastname: Yang
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Terman
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004330:Drosophila; D029721:Drosophila Proteins / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D009434:Neural Pathways / Q000254:growth & development*; D011956:Receptors, Cell Surface / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*; D039961:Semaphorins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D039961:Semaphorins; C116483:plexA protein, Drosophila; C091529:plexin; D020703:ras GTPase-Activating Proteins; D017868:Cyclic AMP-Dependent Protein Kinases