p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance*
Identifieur interne : 001E19 ( Ncbi/Checkpoint ); précédent : 001E18; suivant : 001E20p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance*
Auteurs : Judith Antoine-Bertrand ; Philippe M. Duquette ; Ricardo Alchini ; Timothy E. Kennedy ; Alyson E. Fournier ; Nathalie Lamarche-VaneSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2015.
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.
Url:
DOI: 10.1074/jbc.M115.674846
PubMed: 26710849
PubMed Central: 4813483
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>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.</p>
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<name sortKey="Duquette, Philippe M" sort="Duquette, Philippe M" uniqKey="Duquette P" first="Philippe M." last="Duquette">Philippe M. Duquette</name>
<name sortKey="Fournier, Alyson E" sort="Fournier, Alyson E" uniqKey="Fournier A" first="Alyson E." last="Fournier">Alyson E. Fournier</name>
<name sortKey="Kennedy, Timothy E" sort="Kennedy, Timothy E" uniqKey="Kennedy T" first="Timothy E." last="Kennedy">Timothy E. Kennedy</name>
<name sortKey="Lamarche Vane, Nathalie" sort="Lamarche Vane, Nathalie" uniqKey="Lamarche Vane N" first="Nathalie" last="Lamarche-Vane">Nathalie Lamarche-Vane</name>
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