title: p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance.
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.
authors.affiliation: From the Department of Anatomy and Cell Biology and Cancer Research Program, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec, H4A 3J1 Canada and.
authors.forename: Judith
authors.initials: J
authors.lastname: Antoine-Bertrand
authors.affiliation: From the Department of Anatomy and Cell Biology and Cancer Research Program, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec, H4A 3J1 Canada and.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Duquette
authors.affiliation: the Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, H3A 2B4 Canada.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Alchini
authors.affiliation: the Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, H3A 2B4 Canada.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.affiliation: the Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, H3A 2B4 Canada.
authors.forename: Alyson E
authors.initials: AE
authors.lastname: Fournier
authors.affiliation: From the Department of Anatomy and Cell Biology and Cancer Research Program, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec, H4A 3J1 Canada and nathalie.lamarche@mcgill.ca.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lamarche-Vane
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D002645:Chickens; D000075389:DCC Receptor; D004622:Embryo, Mammalian / Q000166:cytology; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D034622:RNA Interference; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020729:p120 GTPase Activating Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; D050505:Mutant Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C000617354:Ntn1 protein, rat; D010446:Peptide Fragments; C557248:RASA1 protein, human; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D020729:p120 GTPase Activating Protein; D000075388:Netrin-1; D005982:Glutathione Transferase
keywords: DCC; Ras protein; netrin-1; neurite outgrowth; neurobiology; neurodevelopment; signal transduction