Reelin-mediated Signaling Locally Regulates Protein Kinase B/Akt and Glycogen Synthase Kinase 3β
Open accessAbstract
Reelin is a large secreted protein that controls cortical layering by signaling through the very low density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1) and suppressing tau phosphorylation in vivo. Here we show that binding of Reelin to these receptors stimulates phosphatidylinositol 3-kinase, resulting in activation of protein kinase B and inhibition of glycogen synthase kinase 3beta. We present genetic evidence that this cascade is dependent on apolipoprotein E receptor 2, very low density lipoprotein receptor, and Dab1. Reelin-signaling components are enriched in axonal growth cones, where tyrosine phosphorylation of Dab1 is increased in response to Reelin. These findings suggest that Reelin-mediated phosphatidylinositol 3-kinase signaling in neuronal growth cones contributes to final neuron positioning in the mammalian brain by local modulation of protein kinase B and glycogen synthase kinase 3beta kinase activities.
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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 [52]
The introduction states that Reelin binds ApoER2 and VLDLR and induces Dab1 phosphorylation; the Discussion reports downstream PI3K and PKB signaling. Our copy does not say that Reelin induces receptor clustering, so that step in the claimed mechanism is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredKnockout of both ApoER2 and VLDLR proteins is required to prevent reelin-induced phosphorylation of Dab1.
“In fact, it has been shown that knockout of both ApoER2 and VLDLR proteins is required to prevent reelin-induced phosphorylation of Dab1 [52], suggesting that both proteins could be altered in SNX17 knockdown cells.”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [52]
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- Authors
- Beffert, U., Morfini, G., Bock, H. H., Reyna, H., Brady, S. T., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Herz, Joachim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 277
- Issue
- 51
- Pages
- 49958-49964
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1967606063
- Cited by
- 306
- References
- 5
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 8 · 2023: 9 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 4 · 2018: 4 · 2017: 12 · 2016: 15 · 2015: 9 · 2014: 14 · 2013: 16 · 2012: 17
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Welch Foundation
- American Heart Association (HL20948)
- Alexander von Humboldt-Stiftung
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (NS23868, HL20948, HL63762)
- National Heart, Lung, and Blood Institute (HL-20948, HL63762, R37HL063762, P01HL020948)
- National Institute of Neurological Disorders and Stroke (NS 23868, NS43408, R01NS023320, NS41170, R01NS041170, NS 23320, 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, phosphatidylinositol 3-kinase signaling, Akt/protein kinase B, glycogen synthase kinase-3β, ApoER2, VLDLR, Disabled-1, tau phosphorylation, cortical lamination, axonal growth cones, tyrosine phosphorylation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Reelin Protein, Animals, Brain, Cell Line, Enzyme Inhibitors, Homozygote, Humans, Immunohistochemistry, Mice, Inbred C57BL, Models, Biological, Nerve Tissue Proteins, Phosphorylation, Precipitin Tests, Protein Binding, Proto-Oncogene Proteins, Recombinant Proteins, Serine, Serine Endopeptidases, Subcellular Fractions, Threonine, Transfection, Immunoblotting, Signal Transduction, Cell Adhesion Molecules, Neuronal, Gene Expression Regulation, Enzymologic, Extracellular Matrix Proteins, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Mice, Rats
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