The EphA4 receptor regulates dendritic spine remodeling by affecting β1-integrin signaling pathways

• DOI: 10.1083/jcb.200610139
• Publication Date: 2007-09-18T01:04:23Z
• Authors: Caroline Bourgin; Keith K. Murai; Melanie Richter; Elena B. Pasquale
• Keywords: 0303 health sciences; Dendritic Spines; Integrin beta1; Receptor, EphA4; Nerve Tissue Proteins; Proto-Oncogene Proteins c-crk; Phosphoproteins; Proto-Oncogene Proteins c-fyn; Hippocampus; Ephrin-A3; Rats; Enzyme Activation; Mice; 03 medical and health sciences; Crk-Associated Substrate Protein; Cell Adhesion; Animals; Humans; Phosphorylation; Phosphotyrosine; Research Articles; Protein Binding; Signal Transduction

Remodeling of dendritic spines is believed to modulate the function of excitatory synapses. We previously reported that the EphA4 receptor tyrosine kinase regulates spine morphology in hippocampal pyramidal neurons, but the signaling pathways involved were not characterized (Murai, K.K., L.N. Nguyen, F. Irie, Y. Yamaguchi, and E.B. Pasquale. 2003. Nat. Neurosci. 6:153–160). In this study, we show that EphA4 activation by ephrin-A3 in hippocampal slices inhibits integrin downstream signaling pathways. EphA4 activation decreases tyrosine phosphorylation of the scaffolding protein Crk-associated substrate (Cas) and the tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) and also reduces the association of Cas with the Src family kinase Fyn and the adaptor Crk. Consistent with this, EphA4 inhibits β1-integrin activity in neuronal cells. Supporting a functional role for β1 integrin and Cas inactivation downstream of EphA4, the inhibition of integrin or Cas function induces spine morphological changes similar to those associated with EphA4 activation. Furthermore, preventing β1-integrin inactivation blocks the effects of EphA4 on spines. Our results support a model in which EphA4 interferes with integrin signaling pathways that stabilize dendritic spines, thus modulating synaptic interactions with the extracellular environment.