The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways.
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 beta1-integrin activity in neuronal cells. Supporting a functional role for beta1 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 beta1-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.
Bourgin
Caroline
C
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Murai
Keith K
KK
Richter
Melanie
M
Pasquale
Elena B
EB
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000737:chemistry / Q000172:deficiency; D049229:Dendritic Spines / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D036384:Ephrin-A3 / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D051381:Rats; D036122:Receptor, EphA4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D018909:src Homology Domains
D050719:Crk-Associated Substrate Protein; D036384:Ephrin-A3; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D050737:Proto-Oncogene Proteins c-crk; C033652:postsynaptic density proteins; D019000:Phosphotyrosine; D036122:Receptor, EphA4; D051076:Proto-Oncogene Proteins c-fyn