Regulation of Protein Tyrosine Kinase Signaling by Substrate Degradation during Brain Development
Open accessAbstract
Disabled-1 (Dab1) is a cytoplasmic adaptor protein that regulates neuronal migrations during mammalian brain development. Dab1 function in vivo depends on tyrosine phosphorylation, which is stimulated by extracellular Reelin and requires Src family kinases. Reelin signaling also negatively regulates Dab1 protein levels in vivo, and reduced Dab1 levels may be part of the mechanism that regulates neuronal migration. We have made use of mouse embryo cortical neuron cultures in which Reelin induces Dab1 tyrosine phosphorylation and Src family kinase activation. We have found that Dab1 is normally stable, but in response to Reelin it becomes polyubiquitinated and degraded via the proteasome pathway. We have established that tyrosine phosphorylation of Dab1 is required for its degradation. Dab1 molecules lacking phosphotyrosine are not degraded in neurons in which the Dab1 degradation pathway is active. The requirements for Reelin-induced degradation of Dab1 in vitro correctly predict Dab1 protein levels in vivo in different mutant mice. We also provide evidence that Dab1 serine/threonine phosphorylation may be important for Dab1 tyrosine phosphorylation. Our data provide the first evidence for how Reelin down-regulates Dab1 protein expression in vivo. Dab1 degradation may be important for ensuring a transient Reelin response and may play a role in normal brain development.
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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 [44]
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- Authors
- Arnaud, L., Ballif, B. A., & Cooper, J. A.
- Affiliations
- Fred Hutch Cancer Center (US)
- Corresponding author
- Cooper, Jonathan A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-12-01
- Volume
- 23
- Issue
- 24
- Pages
- 9293-9302
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC309695
- OpenAlex
- W2161011016
- Cited by
- 164
- References
- 50
- Citations by year
- 2026: 2 · 2025: 5 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 9 · 2016: 9 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 6
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R37CA041072, R37 CA41072, CA41072)
- 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
- Disabled-1, Dab1, Reelin signaling, tyrosine kinase signaling, protein degradation, polyubiquitination, proteasome, tyrosine phosphorylation, serine/threonine phosphorylation, Src family kinases, neuronal migration, brain development, cortical neurons, adaptor proteins
- MeSH terms
- Reelin Protein, Animals, Brain, Cells, Cultured, Cysteine Endopeptidases, Enzyme Activation, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Neurological, Multienzyme Complexes, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein-Tyrosine Kinases, Serine Endopeptidases, Substrate Specificity, Tyrosine, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, src-Family Kinases, Ubiquitin, Proteasome Endopeptidase Complex, Mice
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