Receptor Clustering Is Involved in Reelin Signaling
Open accessAbstract
The Reelin signaling cascade plays a crucial role in the correct positioning of neurons during embryonic brain development. Reelin binding to apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) leads to phosphorylation of disabled 1 (Dab1), an adaptor protein which associates with the intracellular domains of both receptors. Coreceptors for Reelin have been postulated to be necessary for Dab1 phosphorylation. We show that bivalent agents specifically binding to ApoER2 or VLDLR are sufficient to mimic the Reelin signal. These agents induce Dab1 phosphorylation, activate members of the Src family of nonreceptor tyrosine kinases, modulate protein kinase B/Akt phosphorylation, and increase long-term potentiation in hippocampal slices. Induced dimerization of Dab1 in HEK293 cells leads to its phosphorylation even in the absence of Reelin receptors. The mechanism for and the sites of these phosphorylations are identical to those effected by Reelin in primary neurons. These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR. As a consequence, Dab1 becomes dimerized or oligomerized on the cytosolic side of the plasma membrane, constituting the active substrate for the kinase; this process seems to be sufficient to transmit the signal and does not appear to require any coreceptor.
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Reelin's effects are related to its ability to interact with ApoER2 and VLDLR, inducing their clustering, which results in Dab1 phosphorylation and activation of different effectors.
“These effects are related to reelin's ability to interact with ApoER2 and VLDLR, inducing their clustering [76], which results in Dab1 phosphorylation and the activation of different effectors [52], [77], [78].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [76]
Through these receptors, Reelin activates Dab-1, an intracellular adapter that facilitates signaling between Reelin-secreting cells and pyramidal cells.
“Through these receptors, Reelin is able to activate Disabled1 (Dab-1), an intracellular adapter protein that facilitates signaling between Reelin-secreting cells and pyramidal cells [147].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [147]
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- Authors
- Strasser, V., Fasching, D., Hauser, C., Mayer, H., Bock, H. H., Hiesberger, T., Herz, J., Weeber, E. J., Sweatt, J. D., Pramatarova, A., Howell, B., Schneider, W. J., & Nimpf, J.
- Affiliations
- University of Vienna (AT)
- The University of Texas Southwestern Medical Center (US)
- Baylor College of Medicine (US)
- National Institutes of Health (US)
- Corresponding author
- Nimpf, Johannes
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-02-01
- Volume
- 24
- Issue
- 3
- Pages
- 1378-1386
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC321426
- OpenAlex
- W2109110124
- Cited by
- 193
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 12 · 2016: 12 · 2015: 8 · 2014: 11 · 2013: 8 · 2012: 12
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Herzfelder'sche Familienstiftung
- National Heart, Lung, and Blood Institute (R37HL063762)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Reelin signaling, receptor clustering, ApoER2, VLDLR, Src family kinases, Akt signaling, long-term potentiation, hippocampus, receptor dimerization, co-receptors, neuronal positioning, embryonic brain development
- MeSH terms
- Reelin Protein, Animals, Nerve Tissue Proteins, Receptors, Cell Surface, Serine Endopeptidases, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Dimerization, Rats
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