Taehong Yang

University of Texas at Dallas, Richardson, Texas, United States

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Publications (5)79.91 Total impact

  • Taehong Yang, Jonathan R Terman
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    ABSTRACT: Small GTPases play critical roles in diverse biological events including regulating both the cytoskeletal and adhesive properties of cells. The importance of small GTPases to these events stems from their ability to be turned on and off, respectively, by specific GEFs and GAPs. In neurons, for example, regulation of small GTPase activity by extracellular guidance cues controls axonal and dendritic process shape, extension and navigation. Here, we discuss recent findings that indicate a specific regulator of small GTPase signaling, the Plexin transmembrane GAP, is differentially controlled by specific extracellular cues to guide growing axons. In particular, Plexins are receptors for one of the largest families of axon guidance cues, Semaphorins and negatively regulate cell morphology and motility by serving as GAPs for Ras/Rap family GTPases. Recent observations reveal that Plexin's GAP activity is controlled by the cAMP-dependent protein kinase (PKA), which phosphorylates Plexin and generates a binding site for the phospho-serine/threonine binding protein 14-3-3ε. This PKA-mediated Plexin-14-3-3ε interaction prevents Plexin from associating with its GTPase substrate, and thus antagonizes Semaphorin signaling. We now further examine these interactions and how they provide a new logic by which axon guidance signaling pathways over-ride one another to steer growing axons. We also further explore how Plexin interacting proteins, including Ras, PKA and 14-3-3 may interact with the Plexin GAP domain. Our observations also further indicate that 14-3-3 proteins may have conserved roles in the regulation of GTPase activity.
    Small GTPases 12/2012; 4(1). DOI:10.4161/sgtp.22765
  • Taehong Yang, Jonathan R Terman
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    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.
    Neuron 04/2012; 74(1):108-21. DOI:10.1016/j.neuron.2011.12.034 · 15.98 Impact Factor
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    ABSTRACT: Author Summary Brain wiring is determined by genetic and environmental factors, nature and nurture. The Drosophila brain is a model for the genetic basis of brain wiring. The fly visual system in particular is thought to be “hard-wired,” i.e., encoded solely by a genetic program. Some key genes encode the guidance receptors that serve as “wiring” and synaptic connectivity signals. However, it is poorly understood how guidance receptors are spatiotemporally regulated to serve as meaningful synapse formation signals. Indeed, many genes required for brain wiring do not encode the guidance receptors themselves, but rather encode parts of the cell biological machinery that governs their spatiotemporal signaling dynamics. For example, the vesicular ATPase is an intracellular sorting and acidification complex involved in regulating guidance receptor turnover and signaling. The protein V100 is a member of this v-ATPase complex, and in this study we show that mutations in the v100 gene cause brain wiring defects specifically in the adult brain. We further describe a V100-dependent intracellular “sort-and-degrade” mechanism that is required in neurons, and find that when this mechanism is perturbed, it leads to progressive build-up of and aberrant signaling by guidance receptors. These data suggest that a v100-dependent neuronal degradation mechanism provides a cell biological basis for guidance receptor turnover and spatiotemporally controlled dynamics during neural circuit formation.
    PLoS Biology 12/2010; 8(12):e1000553. DOI:10.1371/journal.pbio.1000553 · 11.77 Impact Factor
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    ABSTRACT: How instructive cues present on the cell surface have their precise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largest families of these instructive cues and are widely studied for their effects on cell movement, navigation, angiogenesis, immunology and cancer. Semaphorins/collapsins were characterized in part on the basis of their ability to drastically alter actin cytoskeletal dynamics in neuronal processes, but despite considerable progress in the identification of semaphorin receptors and their signalling pathways, the molecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highly unusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmic portion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance, synaptogenesis, dendritic pruning and other cell morphological changes. Mical enzymes perform reduction-oxidation (redox) enzymatic reactions and also contain domains found in proteins that regulate cell morphology. However, nothing is known of the role of Mical or its redox activity in mediating morphological changes. Here we report that Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary and sufficient for semaphorin-plexin-mediated F-actin reorganization in vivo. Likewise, we purified Mical protein and found that it directly binds F-actin and disassembles both individual and bundled actin filaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation. Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through which actin reorganization-a hallmark of cell morphological changes including axon navigation-can be precisely achieved spatiotemporally in response to semaphorins.
    Nature 02/2010; 463(7282):823-7. DOI:10.1038/nature08724 · 42.35 Impact Factor
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    ABSTRACT: Plexin cell surface receptors bind to semaphorin ligands and transduce signals for regulating neuronal axon guidance. The intracellular region of plexins is essential for signaling and contains a R-Ras/M-Ras GTPase activating protein (GAP) domain that is divided into two segments by a Rho GTPase-binding domain (RBD). The regulation mechanisms for plexin remain elusive, although it is known that activation requires both binding of semaphorin to the extracellular region and a Rho-family GTPase (Rac1 or Rnd1) to the RBD. Here we report the crystal structure of the plexin A3 intracellular region. The structure shows that the N- and C-terminal portions of the GAP homologous regions together form a GAP domain with an overall fold similar to other Ras GAPs. However, the plexin GAP domain adopts a closed conformation and cannot accommodate R-Ras/M-Ras in its substrate-binding site, providing a structural basis for the autoinhibited state of plexins. A comparison with the plexin B1 RBD/Rnd1 complex structure suggests that Rnd1 binding alone does not induce a conformational change in plexin, explaining the requirement of both semaphorin and a Rho GTPase for activation. The structure also identifies an N-terminal segment that is important for regulation. Both the N-terminal segment and the RBD make extensive interactions with the GAP domain, suggesting the presence of an allosteric network connecting these three domains that integrates semaphorin and Rho GTPase signals to activate the GAP. The importance of these interactions in plexin signaling is shown by both cell-based and in vivo axon guidance assays.
    Proceedings of the National Academy of Sciences 09/2009; 106(37):15610-5. DOI:10.1073/pnas.0906923106 · 9.81 Impact Factor