A secreted soluble form of ApoE receptor 2 acts as a dominant-negative receptor and inhibits Reelin signaling.
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.
Koch
Stefanie
S
The Institute of Medical Biochemistry, Department of Molecular Genetics, BioCenter and University of Vienna, Vienna, Austria.
Strasser
Vera
V
Hauser
Christoph
C
Fasching
Daniela
D
Brandes
Christian
C
Bajari
Tarek M
TM
Schneider
Wolfgang J
WJ
Nimpf
Johannes
J
D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000196:embryology; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism; D045683:Furin; D005799:Genes, Dominant; D006031:Glycosylation; D026541:Heymann Nephritis Antigenic Complex / Q000378:metabolism; D026502:LDL-Receptor Related Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D013381:Subtilisins / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; C113062:DAB1 protein, Neurospora crassa; D016326:Extracellular Matrix Proteins; D005656:Fungal Proteins; D026541:Heymann Nephritis Antigenic Complex; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D011993:Recombinant Fusion Proteins; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D013381:Subtilisins; D045683:Furin