p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance
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The receptor deleted in colorectal cancer (DCC) mediates the attraction of growing axons to netrin-1 during brain development. In response to netrin-1 stimulation, DCC becomes a signaling platform to recruit proteins that promote axon outgrowth and guidance. The Ras GTPase-activating protein (GAP) p120RasGAP inhibits Ras activity and mediates neurite retraction and growth cone collapse in response to repulsive guidance cues. Here we show an interaction between p120RasGAP and DCC that positively regulates netrin-1-mediated axon outgrowth and guidance in embryonic cortical neurons. In response to netrin-1, p120RasGAP is recruited to DCC in growth cones and forms a multiprotein complex with focal adhesion kinase and ERK. We found that Ras/ERK activities are elevated aberrantly in p120RasGAP-deficient neurons. Moreover, the expression of p120RasGAP Src homology 2 (SH2)-SH3-SH2 domains, which interact with the C-terminal tail of DCC, is sufficient to restore netrin-1-dependent axon outgrowth in p120RasGAP-deficient neurons. We provide a novel mechanism that exploits the scaffolding properties of the N terminus of p120RasGAP to tightly regulate netrin-1/DCC-dependent axon outgrowth and guidance.
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NOVA1 and RASA1 are known to interact with DCC.
“are known to interact with DCC [111, 112]”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [112]
RASA1 has been shown to mediate Netrin 1-induced cortical axon outgrowth and guidance.
“has been shown to mediate Netrin 1-induced cortical axon outgrowth and guidance [112]”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [112]
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p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts
Bonanomi, D., Valenza, F., Chivatakarn, O., Sternfeld, M. J., Driscoll, S. P., Aslanian, A., Lettieri, K., Gullo, M., Badaloni, A., Lewcock, J. W., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.034 · Cited by 22 · see citing works
Chehayeb, R. J., Stiegler, A. L., & Boggon, T. J. (2019) · PLoS ONE · doi:10.1371/journal.pone.0226113 · Cited by 16 · see citing works
Regulation of Rap GTPases in mammalian neurons
Shah, B., & Püschel, A. W. (2016) · Biological Chemistry · doi:10.1515/hsz-2016-0165 · Cited by 13 · see citing works
Duquette, P. M., & Lamarche‐Vane, N. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14837 · Cited by 10 · see citing works
FGF-Mediated Axon Guidance: Role of Downstream Signaling Pathways in Cytoskeletal Control
Li, J., Gao, H., & Liu, F. (2025) · Cells · doi:10.3390/cells14110777 · Cited by 9 · see citing works
Wang, Y., Zhao, J., Guo, Q., Yin, Y., Tian, W., Wang, X., Deng, G., Pan, Q., & Ma, X. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115224 · Cited by 7 · see citing works
TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branchingPreprint
Plooster, M., Menon, S., Winkle, C. C., Urbina, F., Monkiewicz, C., Phend, K. D., Weinberg, R. J., & Gupton, S. L. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/154666 · Cited by 2 · see citing works
- Authors
- Antoine-Bertrand, J., Duquette, P. M., Alchini, R., Kennedy, T. E., Fournier, A. E., & Lamarche-Vane, N.
- Affiliations
- McGill University Health Centre (CA)
- Montreal Neurological Institute and Hospital (CA)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 291
- Issue
- 9
- Pages
- 4589-4602
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4813483
- OpenAlex
- W2282216642
- Cited by
- 12
- References
- 89
- Citations by year
- 2025: 2 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 4 · 2016: 1
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-14701)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- p120RasGAP, netrin-1, DCC receptor, axon guidance, axon growth, cortical neurons, growth cones, focal adhesion kinase, ERK signaling, Ras GTPase-activating protein, protein scaffolding, embryonic brain development
- MeSH terms
- Netrin-1, DCC Receptor, Animals, Axons, Cells, Cultured, Cerebral Cortex, Chickens, Embryo, Mammalian, Glutathione Transferase, Humans, Nerve Growth Factors, Nerve Tissue Proteins, Neurons, Peptide Fragments, Receptors, Cell Surface, Recombinant Fusion Proteins, Recombinant Proteins, Signal Transduction, Amino Acid Substitution, p120 GTPase Activating Protein, Protein Transport, Tumor Suppressor Proteins, RNA Interference, Mutant Proteins, Rats, Protein Interaction Domains and Motifs, HEK293 Cells
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