Ephrin-Eph signaling plays critical roles in diverse processes in both developing and mature nervous system. For example, EphA4 activation regulates the dendritic spine density in hippocampal neurons. However, the underlying mechanisms that regulate Eph expression and their intracellular fate are unclear. Using yeast-two hybrid screening, we have previously identified the interaction of EphA4 with APC2i, an isoform of APC2 which is one of the major components of anaphase promoting complex (APC). The APC was first identified to be a multi-subunit ubiquitin ligase that controls the degradation of cell cycle regulatory proteins. However, recent emerging studies suggest that the APC may control protein degradation in neurons. In particular, the APC activator Cdh1 regulates the development a...[ Read more ]

Ephrin-Eph signaling plays critical roles in diverse processes in both developing and mature nervous system. For example, EphA4 activation regulates the dendritic spine density in hippocampal neurons. However, the underlying mechanisms that regulate Eph expression and their intracellular fate are unclear. Using yeast-two hybrid screening, we have previously identified the interaction of EphA4 with APC2i, an isoform of APC2 which is one of the major components of anaphase promoting complex (APC). The APC was first identified to be a multi-subunit ubiquitin ligase that controls the degradation of cell cycle regulatory proteins. However, recent emerging studies suggest that the APC may control protein degradation in neurons. In particular, the APC activator Cdh1 regulates the development and survival of postmitotic neurons. In this study, we report that EphA4 protein expression may be regulated by the APC^Cdh1-mediated ubiquitin-proteasome degradation pathway. We showed that EphA4 interacts with different components of APC including APC2 and Cdh1. In addition, we showed that the surface as well as total expression of EphA4 is down-regulated by the overexpressed Cdh1 in HEK293T cells. Furthermore, we found that ephrin-A1 treatment promote the ubiquitination of EphA4 in neurons, leading to a reduction in the surface expression of EphA4, which is attenuated by proteasome inhibitor. Together, our findings suggest that EphA4 expression in neurons is regulated by APC^Cdh1-mediated ubiquitin-proteasome degradation pathway, which may play a role in EphA4-mediated signaling in neurons.