TY - JOUR
T1 - EphB2 receptor forward signaling controls cortical growth cone collapse via Nck and Pak
AU - Srivastava, Nishi
AU - Robichaux, Michael A.
AU - Chenaux, George
AU - Henkemeyer, Mark
AU - Cowan, Christopher W.
N1 - Funding Information:
The authors would like to thank Dr. Michael Greenberg for generously sharing various published antibodies and plasmids generated in his lab, and we acknowledge Addgene for numerous Pak1, Pak5, RhoA, Rac, and Cdc42 plasmids. We also thank Dr. Louise Larose for the generous gift of Nck1 WT and mutant expression plasmids. Purified GST-PBD protein was provided by the NEI-funded Recombinant Protein and Virus Core ( P30 EY020799 ). M.A.R. was supported by a training grant from NIDA ( T32 DA07290 ). We acknowledge the generous support of the Whitehall Foundation (C.W.C.), and grants from the National Institutes of Health ( RO1 EY018207 to C.W.C.) and ( RO1 MH66332 to M.H.).
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
KW - Axon guidance
KW - Eph receptor
KW - Ephrin
KW - Growth cone
KW - Signal transduction
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U2 - 10.1016/j.mcn.2012.11.003
DO - 10.1016/j.mcn.2012.11.003
M3 - Article
C2 - 23147113
AN - SCOPUS:84870371563
SN - 1044-7431
VL - 52
SP - 106
EP - 116
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
ER -