Reelin-signaling and Receptor Dimerization

Specialized neurons throughout the developing central nervous system secrete Reelin, which binds to ApoE receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) triggering a signal cascade which guides neurons to their correct position. Binding of Reelin to ApoER2 and VLDLR induces phosphorylation of Dab1, which binds to the intracellular domains of both receptors. Further downstream events and the kinase(s) responsible for phosphorylation of Dab1 are not characterized yet. Involvement of co-receptors for Reelin have been postulated but their mode of action ist still not resolved. Preliminary experiments in our laboratory suggest that reelin induces the dimerization or clustering of ApoER2 and VLDLR which might be sufficient for the phosphorylation of Dab1. Furthermore, PDGF-BB seems to be another ligand for ApoER2 and VLDLR and might be directly involved in transducing the Reelin signal. The major aims of this project are i) to characterize the interaction of Reelin with ApoER2 and VLDLR and to evaluate whether receptor clustering is sufficient for Dab1 phsphorylation; ii) to evaluate whether ApoER2 and VLDL receptor become phosphorylated upon reelin stimulation and whether dissociation of phosphorylated Dab1 from the receptors is a part of the reelin signaling pathway; and iii) to define the role of PDGF-BB in Reelin- signaling. We are confident that the experiments proposed in this project will result in a significant step forward in understanding key aspects of the Reelin signaling pathway at the cellular level.

Specialized neurons throughout the developing central nervous system secrete Reelin, which binds to ApoE receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) triggering a signal cascade which guides neurons to their correct position. Binding of Reelin to ApoER2 and VLDLR induces phosphorylation of Dab1, which binds to the intracellular domains of both receptors. Further downstream events and the kinase(s) responsible for phosphorylation of Dab1 are not characterized yet. Involvement of co-receptors for Reelin have been postulated but their mode of action ist still not resolved. Preliminary experiments in our laboratory suggest that reelin induces the dimerization or clustering of ApoER2 and VLDLR which might be sufficient for the phosphorylation of Dab1. Furthermore, PDGF-BB seems to be another ligand for ApoER2 and VLDLR and might be directly involved in transducing the Reelin signal. The major aims of this project are i) to characterize the interaction of Reelin with ApoER2 and VLDLR and to evaluate whether receptor clustering is sufficient for Dab1 phsphorylation; ii) to evaluate whether ApoER2 and VLDL receptor become phosphorylated upon reelin stimulation and whether dissociation of phosphorylated Dab1 from the receptors is a part of the reelin signaling pathway; and iii) to define the role of PDGF-BB in Reelin- signaling. We are confident that the experiments proposed in this project will result in a significant step forward in understanding key aspects of the Reelin signaling pathway at the cellular level.