Abstract：
Dab1 is an intracellular adaptor protein essential for brain formation during development. Tyrosine phosphorylation in Dab1 plays important roles in neuronal migration, dendrite development, and synapse formation by affecting several downstream pathways. Reelin is the best-known extracellular protein that induces Dab1 phosphorylation. However, whether other upstream molecule(s) contribute to Dab1 phosphorylation remains largely unknown. Here, we found that EphA4, a member of the Eph family of receptor-type tyrosine kinases, induced Dab1 phosphorylation when co-expressed in cultured cells. Tyrosine residues phosphorylated by EphA4 were the same as those phosphorylated by Reelin in neurons. The autophosphorylation of EphA4 was necessary for Dab1 phosphorylation. We also found that EphA4-induced Dab1 phosphorylation was mediated by the activation of the Src family tyrosine kinases. Interestingly, Dab1 phosphorylation was not observed when EphA4 was activated by ephrin-A5 in cultured cortical neurons, suggesting that Dab1 is localized in a different compartment in them. EphA4-induced Dab1 phosphorylation may occur under limited and/or pathological conditions in the brain.
摘要：
Dab1是发育过程中脑形成所必需的细胞内衔接蛋白。酪氨酸磷酸化Dab1在神经元迁移中起重要作用，枝晶发展，和突触形成通过影响几个下游途径。Reelin是诱导Dab1磷酸化的最著名的细胞外蛋白。然而,其他上游分子是否有助于Dab1磷酸化仍在很大程度上未知。这里,我们发现EphA4是Eph受体型酪氨酸激酶家族的成员，在培养细胞中共表达时诱导Dab1磷酸化。EphA4磷酸化的酪氨酸残基与神经元中Reelin磷酸化的酪氨酸残基相同。EphA4的自磷酸化对于Dab1磷酸化是必需的。我们还发现EphA4诱导的Dab1磷酸化是由Src家族酪氨酸激酶的激活介导的。有趣的是,当EphA4在培养的皮质神经元中被ephrin-A5激活时，未观察到Dab1磷酸化，表明Dab1位于它们的不同隔室中。EphA4诱导的Dab1磷酸化可以在脑中的有限和/或病理条件下发生。
