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

• Published in: The Journal of biological chemistry 2016-02, Vol.291 (9), p.4589-4602
• Main Authors: Antoine-Bertrand, Judith, Duquette, Philippe M., Alchini, Ricardo, Kennedy, Timothy E., Fournier, Alyson E., Lamarche-Vane, Nathalie
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Axons - metabolism; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Chickens; DCC; DCC Receptor; Embryo, Mammalian - cytology; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; HEK293 Cells; Humans; Mutant Proteins - agonists; Mutant Proteins - genetics; Mutant Proteins - metabolism; Nerve Growth Factors - antagonists & inhibitors; Nerve Growth Factors - chemistry; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Netrin-1; neurite outgrowth; Neurobiology; neurodevelopment; Neurons - cytology; Neurons - metabolism; p120 GTPase Activating Protein - antagonists & inhibitors; p120 GTPase Activating Protein - chemistry; p120 GTPase Activating Protein - genetics; p120 GTPase Activating Protein - metabolism; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Protein Interaction Domains and Motifs; Protein Transport; Ras protein; Rats; Receptors, Cell Surface - agonists; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; RNA Interference; Signal Transduction; Tumor Suppressor Proteins - agonists; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.674846

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.