Differential Functions of ApoER2 and Very Low Density Lipoprotein Receptor in Reelin Signaling Depend on Differential Sorting of the Receptors

Abstract

ApoER2 and very low density lipoprotein (VLDL) receptor transmit the Reelin signal into target cells of the central nervous system. To a certain extent, both receptors can compensate for each other, and only the loss of both receptors results in the reeler phenotype, which is characterized by a gross defect in the architecture of laminated brain structures. Nevertheless, both receptors also have specific distinct functions, as corroborated by analyses of the subtle phenotypes displayed in mice lacking either ApoER2 or VLDL receptor. The differences in their function(s), however, have not been defined at the cellular level. Here, using a panel of chimeric receptors, we demonstrate that endocytosis of Reelin and the fate of the individual receptors upon stimulation are linked to their specific sorting to raft versus non-raft domains of the plasma membrane. VLDL receptor residing in the non-raft domain endocytoses and destines Reelin for degradation via the clathrin-coated pit/clathrin-coated vesicle/endosome pathway without being degraded to a significant extent. Binding of Reelin to ApoER2, a resident of rafts, leads to the production of specific receptor fragments with specific functions of their own and to degradation of ApoER2 via lysosomes. These features contribute to a receptor-specific fine tuning of the Reelin signal, leading to a novel model that emphasizes negative feedback loops specifically mediated by ApoER2 and VLDL receptor, respectively.

Cleavage within Reelin Repeat 3 Regulates the Duration and Range of the Signaling Activity of Reelin Protein

“…These results indicate that endocytosed Reelin maintains its ability to induce Dab1 phosphorylation even in intracellular compartments and that N-t cleavage and its subsequent clearance are indispensable aspects of halting downstream Reelin signaling. It has been shown previously that endocytosis of the Reelin-receptor complex is not a prerequisite for Dab1 phosphorylation (35,36). However, it was unknown whether or not endocytosed Reelin retains its activity.…”

“…However, it was unknown whether or not endocytosed Reelin retains its activity. In transfected NIH3T3 cells, Reelin binding to ApoER2 and VLDLR resulted in alterations in their intracellular trafficking, with ApoER2 tending toward degradation, whereas VLDLR was recycled back to the plasma membrane (36). In both cases, Reelin was degraded in the endosome (36).…”

“…This event is an essential component of Reelin signaling (33,34). Reelin is internalized in an ApoER2/ VLDLR-dependent manner (24,28), but this is not necessary for Dab1 phosphorylation (35,36). We showed previously that N-t cleavage virtually abolishes the ability of Reelin to induce Dab1 phosphorylation (10).…”

Clusterin Is a Ligand for Apolipoprotein E Receptor 2 (ApoER2) and Very Low Density Lipoprotein Receptor (VLDLR) and Signals via the Reelin-signaling Pathway

“…In fibroblasts expressing VLDLR and Dab1 this effect is less pronounced. The reason for this difference is not yet clear but might be caused by differential sorting of the receptors to rafts and non-raft domains in the fibroblast model (44).…”

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

“…(34,(36)(37)(38) Interaction between LRP8 and Reelin also initiates internalization of Reelin in the clathrin-mediated endocytosis pathway. (39) LRP8 single-knockout mice were grossly normal, but showed reduced male fertility and suffered accelerated cell death during normal aging 4,35 ; LRP8 and VLDLR double-knockout mice displayed disorganized neurons, and cortical lamination was affected in brain development. (35) As a receptor for apolipoprotein E, the LRP8 gene polymorphism might associate with the developing Alzheimer's disease (AD).…”