Apolipoprotein E Receptors Are Required for Reelin-induced Proteasomal Degradation of the Neuronal Adaptor Protein Disabled-1
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The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nckbeta. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dab1 degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.
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In wild-type neurons, NOVA2 represses both exon 7b and 7c of the Dab1 transcript, and the resulting DAB1 protein isoform DAB1Δ7bc is subject to ubiquitylation upon Reelin activation.
“In wild-type neurons, NOVA2 represses both exon 7b and 7c of the Dab1 transcript, and the resulting DAB1 protein isoform DAB1Δ7bc is subject to ubiquitylation upon Reelin activation43–45.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [45]
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- Authors
- Bock, H. H., Jossin, Y., May, P., Bergner, O., & Herz, J.
- Affiliations
- University of Freiburg (DE)
- UCLouvain (BE)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Bock, Hans H.
- Herz, Joachim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-08
- Volume
- 279
- Issue
- 32
- Pages
- 33471-33479
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1988962037
- Cited by
- 102
- References
- 62
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 5 · 2012: 3
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-20948, HL63762, R37HL063762, P01HL020948)
- National Institute of Neurological Disorders and Stroke (NS43408, R01NS043408)
- 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, Disabled-1, apolipoprotein E receptor, ApoER2, VLDLR, proteasomal degradation, ubiquitin-proteasome system, tyrosine phosphorylation, Fyn, PI3-kinase, neuronal positioning, brain development, synaptic transmission
- MeSH terms
- Reelin Protein, Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Cerebral Cortex, Cysteine Endopeptidases, Embryo, Mammalian, Enzyme Inhibitors, Humans, Immunohistochemistry, Mice, Inbred C57BL, Molecular Sequence Data, Multienzyme Complexes, Mutation, Nerve Tissue Proteins, Neurons, Phosphorylation, Proto-Oncogene Proteins, Receptors, LDL, Recombinant Fusion Proteins, RNA, Messenger, Serine Endopeptidases, Transfection, Tyrosine, Signal Transduction, Cell Adhesion Molecules, Neuronal, Polymerase Chain Reaction, Extracellular Matrix Proteins, Rats, Sprague-Dawley, src-Family Kinases, Phosphatidylinositol 3-Kinases, Ubiquitin, Low Density Lipoprotein Receptor-Related Protein-1, Culture Techniques, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-fyn, Mice, Rats
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