Characterizing the Molecular Mechanisms of Axon Guidance: Activation and Regulation of the Axon Guidance Receptor Plexin A

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Title: Characterizing the Molecular Mechanisms of Axon Guidance: Activation and Regulation of the Axon Guidance Receptor Plexin A
Author: Yang, Taehong Yang
Abstract: Neuronal connectivity is precisely determined by axonal pathfinding during development . The navigating axons detect attractive and repulsive environmental cues by axon guidance receptors . However , the biochemical means through which multiple signaling pathways are integrated in navigating axons is poorly understood . Semaphorins are the largest family of axon guidance cues and utilize Plexin receptors to exert repulsive effects on axon extension . The intracellular region of Plexins contains a Ras GTPase activating protein (GAP ) domain , which is necessary for repulsive guidance effects . Previous studies suggest that activation of Plexin RasGAP requires interactions with both Semaphorin at the extracellular region and a Rho -family GTPase at the Rho family GTPase -binding domain (RBD ) . Interestingly , Semaphorin repulsion can be rapidly "turned -off" by other distinct cues and signaling cascades . However , the molecular mechanisms to activate or modulate Plexin RasGAP remain unclear . First , to further understand how the Plexin RasGAP is activated , I collaborated with the Zhang lab , and following determination of the crystal structure of the intracellular region of Plexin , I examined the roles of residues interfacing with the RasGAP domain using functional mutagenesis in the Drosophila model system . Our results demonstrate that Plexin exhibits an auto -inhibited conformation , and suggest that interaction among the previously uncharacterized juxtamembrane segment , the RBD , and the RasGAP domain is critical for Plexin RasGAP activation . Second , to better understand how Semaphorin /Plexin signaling is modulated , I characterized the results of a large -scale screen to look for proteins interacting with the cytoplasmic portion of Plexin and identified the phosphoserine binding protein 14 -3 -3epsilon as a specific Plexin -interacting protein . My results reveal that 14 -3 -3epsilon is specifically required for axon guidance during development . Moreover , Protein kinase A is found to phosphorylate Plexin in the RasGAP domain and mediates the 14 -3 -3epsilon interaction . Plexin -14 -3 -3epsilon interactions prevent Plexin from interacting with its Ras -family GTPase substrate , which effectively switches Plexin -mediated axonal repulsion to Integrin -mediated adhesion . These findings uncover both a new molecular integration point between important axon guidance signaling pathways and a biochemical logic by which this guidance information is coalesced to steer the growing axon . Therefore , these new observations on activating and silencing specific signals that are repulsive to axon growth also illuminate new approaches to neutralize axonal growth inhibition and encourage axon regeneration .
URI: http : / /hdl .handle .net /2152 .5 /1009
Date: 2012-07-17

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Characterizing the Molecular Mechanisms of Axon Guidance: Activation and Regulation of the Axon Guidance Receptor Plexin A. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /1009 .

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