title: EphB2 receptor forward signaling controls cortical growth cone collapse via Nck and Pak.
abstract: EphB receptors and their ephrinB ligands transduce bidirectional signals that mediate contact-dependent axon guidance primarily by promoting growth cone repulsion. However, how EphB receptor-mediated forward signaling induces axonal repulsion remains poorly understood. Here, we identify Nck and Pak proteins as essential forward signaling components of EphB2-dependent growth cone collapse in cortical neurons. We show that kinase-active EphB2 binds to Pak and promotes growth cone repulsion via Pak kinase activity, Pak-Nck binding, RhoA signaling and endocytosis. However, Pak's function in this context appears to be independent of Rac/Cdc42-GTP, consistent with the absence of Rac-GTP production after ephrinB treatment of cortical neurons. Taken together, our findings suggest that ephrinB-activated EphB2 receptors recruit a novel Nck/Pak signaling complex to mediate repulsive cortical growth cone guidance, which may be relevant for EphB forward signaling-dependent axon guidance in vivo.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States.
authors.forename: Nishi
authors.initials: N
authors.lastname: Srivastava
authors.forename: Michael A
authors.initials: MA
authors.lastname: Robichaux
authors.forename: George
authors.initials: G
authors.lastname: Chenaux
authors.forename: Mark
authors.initials: M
authors.lastname: Henkemeyer
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D036342:Ephrins / Q000378:metabolism; D055879:Gene Knock-In Techniques; D020439:Growth Cones / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D015513:Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D036183:Receptor, EphB2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036342:Ephrins; C078332:Nck protein; D015513:Oncogene Proteins; D036183:Receptor, EphB2; D054462:p21-Activated Kinases