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A secreted soluble form of ApoE receptor 2 acts as a dominant‐negative receptor and inhibits Reelin signaling
Author(s) -
Koch Stefanie,
Strasser Vera,
Hauser Christoph,
Fasching Daniela,
Brandes Christian,
Bajari Tarek M.,
Schneider Wolfgang J.,
Nimpf Johannes
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf599
Subject(s) - reelin , biology , furin , dab1 , low density lipoprotein receptor related protein 8 , receptor , gene isoform , microbiology and biotechnology , ldl receptor , phosphorylation , alternative splicing , biochemistry , lipoprotein , very low density lipoprotein , gene , cholesterol , enzyme
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 that 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. Due to differential splicing, several isoforms of ApoER2 differing in their ligand‐binding and intracellular domains exist. One isoform harbors four binding repeats plus an adjacent short 13 amino acid insertion containing a furin cleavage site. It is not known whether furin processing of this ApoER2 variant actually takes place and, if so, whether the produced fragment is secreted. Here we demonstrate that cleavage of this ApoER2 variant does indeed take place, and that the resulting receptor fragment consisting of the entire ligand‐binding domain is secreted as soluble polypeptide. This receptor fragment inhibits Reelin signaling in primary neurons, indicating that it can act in a dominant‐negative fashion in the regulation of Reelin signaling during embryonic brain development.