A Secreted Soluble Form of ApoE Receptor 2 Acts As a Dominant-negative Receptor and Inhibits Reelin Signaling

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2002 Nov 12

PMID 12426372

Citations 45

Authors

Stefanie Koch

Vera Strasser

Christoph Hauser

Daniela Fasching

Christian Brandes

Tarek M Bajari

Wolfgang J Schneider

Johannes Nimpf

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Regulation of the hippocampal translatome by Apoer2-ICD release.

Wasser C, Werthmann G, Hall E, Kuhbandner K, Wong C, Durakoglugil M Mol Neurodegener. 2023; 18(1):62.

PMID: 37726747 PMC: 10510282. DOI: 10.1186/s13024-023-00652-1.

Apoer2-ICD-dependent regulation of hippocampal ribosome mRNA loading.

Wasser C, Werthmann G, Hall E, Kuhbandner K, Wong C, Durakoglugil M Res Sq. 2023; .

PMID: 37461529 PMC: 10350194. DOI: 10.21203/rs.3.rs-3040567/v1.

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer's Disease Patients.

Lopez-Font I, Lennol M, Iborra-Lazaro G, Zetterberg H, Blennow K, Saez-Valero J Int J Mol Sci. 2022; 23(14).

PMID: 35886870 PMC: 9318932. DOI: 10.3390/ijms23147522.

Human APOER2 Isoforms Have Differential Cleavage Events and Synaptic Properties.

Omuro K, Gallo C, Scrandis L, Ho A, Beffert U J Neurosci. 2022; 42(20):4054-4068.

PMID: 35414534 PMC: 9121830. DOI: 10.1523/JNEUROSCI.1800-21.2022.

Single molecule, long-read Apoer2 sequencing identifies conserved and species-specific splicing patterns.

Gallo C, Labadorf A, Ho A, Beffert U Genomics. 2022; 114(2):110318.

PMID: 35192893 PMC: 8978334. DOI: 10.1016/j.ygeno.2022.110318.

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