The Caenorhabditis elegans Eph receptor activates NCK and N-WASP, and inhibits Ena/VASP to regulate growth cone dynamics during axon guidance
In: PLoS Genetics, Jg. 8 (2012), Heft 2
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Zugriff:
The Eph receptor tyrosine kinases (RTKs) are regulators of cell migration and axon guidance. However, our understanding of the molecular mechanisms by which Eph RTKs regulate these processes is still incomplete. To understand how Eph receptors regulate axon guidance in Caenorhabditis elegans, we screened for suppressors of axon guidance defects caused by a hyperactive VAB-1/Eph RTK. We identified NCK-1 and WSP-1/N-WASP as downstream effectors of VAB-1. Furthermore, VAB-1, NCK-1, and WSP-1 can form a complex in vitro. We also report that NCK-1 can physically bind UNC-34/Enabled (Ena), and suggest that VAB-1 inhibits the NCK-1/UNC-34 complex and negatively regulates UNC-34. Our results provide a model of the molecular events that allow the VAB-1 RTK to regulate actin dynamics for axon guidance. We suggest that VAB-1/Eph RTK can stop axonal outgrowth by inhibiting filopodia formation at the growth cone by activating Arp2/3 through a VAB-1/NCK-1/WSP-1 complex and by inhibiting UNC-34/Ena activity.
Author Summary The correct wiring of the nervous system depends on the ability of axons to properly interpret extracellular cues that guide them to their targets. The Eph receptor tyrosine kinases (RTKs) have roles in guiding axons, but their signaling pathways are not completely understood. In this study, we used the nematode Caenorhabditis elegans to study how the VAB-1 Eph RTK regulates the growth cone structure for axon guidance. Genetic and molecular data show that VAB-1 regulates the conserved molecules NCK-1, WSP-1/N-WASP, and UNC-34/Ena. Our study provides a model of how the VAB-1 Eph RTK modulates the growth cone structure to inhibit axonal outgrowth. We show that activated VAB-1 can inhibit an NCK-1/UNC-34 interaction by binding to the NCK-1 SH2 domain. We also show that NCK-1 and WSP-1 can physically interact and that VAB-1/NCK-1 and WSP-1 form a complex in vitro. We suggest that the VAB-1 Eph RTK can contribute to the termination of axon outgrowth by two methods: 1) The VAB-1/NCK-1/WSP-1 complex activates ARP-2/3 to change the actin growth cone dynamics to that of a branched structure thus reducing the number of filopodia, and 2) VAB-1 inhibits axon extension by inhibiting UNC-34/Ena's function in actin polymerization.
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The Caenorhabditis elegans Eph receptor activates NCK and N-WASP, and inhibits Ena/VASP to regulate growth cone dynamics during axon guidance
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Autor/in / Beteiligte Person: | Boudreau, Jeffrey R. ; Chin-Sang, Ian D. ; Mohamed, Ahmed M. ; Yu, Fabian P. S. ; Liu, Jun |
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Zeitschrift: | PLoS Genetics, Jg. 8 (2012), Heft 2 |
Veröffentlichung: | Public Library of Science (PLoS), 2012 |
Medientyp: | unknown |
ISSN: | 1553-7404 (print) ; 1553-7390 (print) |
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