Taehong Yang

University of Texas Southwestern Medical Center, Dallas, TX, United States

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Publications (5)76.86 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).
  • 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. · 15.77 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. · 38.60 Impact Factor
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    ABSTRACT: Axon pathfinding and synapse formation rely on precise spatiotemporal localization of guidance receptors. However, little is known about the neuron-specific intracellular trafficking mechanisms that underlie the sorting and activity of these receptors. Here we show that loss of the neuron-specific v-ATPase subunit a1 leads to progressive endosomal guidance receptor accumulations after neuronal differentiation. In the embryo and in adult photoreceptors, these accumulations occur after axon pathfinding and synapse formation is complete. In contrast, receptor missorting occurs sufficiently early in neurons of the adult central nervous system to cause connectivity defects. An increase of guidance receptors, but not of membrane proteins without signaling function, causes specific gain-of-function phenotypes. A point mutant that promotes sorting but prevents degradation reveals spatiotemporally specific guidance receptor turnover and accelerates developmental defects in photoreceptors and embryonic motor neurons. Our findings indicate that a neuron-specific endolysosomal degradation mechanism is part of the cell biological machinery that regulates guidance receptor turnover and signaling.
    PLoS Biology 01/2010; 8(12):e1000553. · 12.69 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. · 9.81 Impact Factor