Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development
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Background The extracellular protein Reln controls neuronal migrations in parts of the cortex, hippocampus and cerebellum. In vivo, absence of Reln correlates with up-regulation of the docking protein Dab1 and decreased Dab1 tyrosine phosphorylation. Loss of the Reln receptor proteins, apolipoprotein receptor 2 and very low density lipoprotein receptor, results in a Reln-like phenotype accompanied by increased Dab1 protein expression. Complete loss of Dab1, however, recapitulates the Reln phenotype. Results To determine whether Dab1 tyrosine phosphorylation affects Dab1 protein expression and positioning of embryonic neurons, we have identified Dab1 tyrosine phosphorylation sites. We then generated mice in which the Dab1 protein had all the potential tyrosine phosphorylation sites mutated. This mutant protein is not tyrosine phosphorylated during brain development and is not upregulated to the extent observed in the Reln or the apoER2 and VLDLR receptor mutants. Animals expressing the non-phosphorylated Dab1 protein have a phenotype similar to the dab1-null mutant. Conclusions Dab1 is downregulated by the Reln signal in neurons in the absence of tyrosine phosphorylation. Dab1 tyrosine phosphorylation sites and not downregulation of Dab1 protein are required for Reln signaling.
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Reelin binding to ApoER2 induces binding of Dab1 to its cytoplasmic NPxY motif, resulting in phosphorylation of specific tyrosines, PI3K activation, and n-cofilin phosphorylation in leading processes of migrating neurons.
“Reelin binding to ApoER2 induces binding of the adaptor protein Dab1 to its cytoplasmic NPxY motif [10], [11], resulting in the phosphorylation of specific tyrosines [12], [13], PI3K activation, and n-cofilin phosphorylation in the leading processes of migrating neurons [9], [14].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [12]
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Reelin Is a Ligand for Lipoprotein Receptors
D'Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D. S., Sheldon, M., & Curran, T. (1999) · Neuron · doi:10.1016/s0896-6273(00)80860-0 · Cited by 808 · cited 2× · see citing works
“The extracellular domains of the LDLR family proteins apolipoprotein receptor 2 (apoER2) and very low density lipoprotein receptor (VLDLR) bind to a variety of extracellular molecules, including apoE-containing lipoproteins and the Reln protein, which they transport into cells via coated pits [29,30].”
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Self-citation
- Authors
- Howell, B. W., Herrick, T. M., Hildebrand, J. D., Zhang, Y., & Cooper, J. A.
- Affiliations
- National Institutes of Health (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Howell, Brian W.
- Cooper, Jonathan A.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 10
- Issue
- 15
- Pages
- 877-885
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2148066913
- Cited by
- 258
- References
- 6
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 13 · 2012: 13
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R37CA041072, 5P30-CA15704-26, P30CA015704)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Dab1, tyrosine phosphorylation sites, reelin, VLDLR, neuronal migration, brain development
- MeSH terms
- Reelin Protein, Amino Acid Sequence, Animals, Brain, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Neurologic Mutants, Molecular Sequence Data, Nerve Tissue Proteins, Phosphorylation, Serine Endopeptidases, Tyrosine, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Gene Expression Regulation, Developmental, Amino Acid Motifs, Mice
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