VEGF activates NR2B phosphorylation through Dab1 pathway.

Vascular endothelial growth factor (VEGF) and reelin are two major signaling pathways involved in many neuronal functions including neurogenesis and neuronal migration. Both VEGF and reelin have been shown to regulate NMDA type glutamate receptor (NMDAR) activity via independent mechanisms. However, it is not known whether the above signaling pathways influence each other on NMDAR regulation. We demonstrate that Disabled 1 (Dab1), a downstream signaling molecule of reelin pathway mediates VEGF-induced regulation of NMDAR subunit NR2B. Furthermore, VEGF treatment led to the association of VEGF receptor-2 (Flk1) and reelin receptor (apolipoprotein E receptor 2, ApoER2), and Dab1 as well as NR2B activation were Flk1-dependent. Moreover, VEGF treatment could significantly rescue the deficits in phospho-Dab1 levels in reeler (Reln-/-) neurons. Our results suggest a major role of VEGF in the regulation of reelin signaling, and Dab1 as a key molecule in the cross talk between reelin and VEGF signaling pathways.