Cited by 12Axon Guidance and Neuronal SignalingNeurogenesis and neuroplasticity mechanismsNerve injury and regeneration

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

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Antoine-Bertrand, Judith, Duquette, Philippe M., Alchini, Ricardo, Kennedy, Timothy E., Fournier, Alyson E., Lamarche-Vane, Nathalie·2016·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m115.674846

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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)
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
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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