Tyrosine phosphorylation of the Rho guanine nucleotide exchange factor Trio regulates netrin-1/DCC-mediated cortical axon outgrowth
| Autor: | Jonathan DeGeer, Jérôme Boudeau, Fiona Bedford, Nathalie Lamarche-Vane, Susanne Schmidt, Anne Debant |
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| Rok vydání: | 2012 |
| Předmět: |
rac1 GTP-Binding Protein
animal structures Deleted in Colorectal Cancer Neurite Nerve Tissue Proteins Receptors Cell Surface Biology Proto-Oncogene Proteins c-fyn Cell Line chemistry.chemical_compound FYN Netrin Neurites Animals Guanine Nucleotide Exchange Factors Humans Nerve Growth Factors Phosphorylation Growth cone Molecular Biology Cells Cultured Cerebral Cortex Tumor Suppressor Proteins fungi Tyrosine phosphorylation Cell Biology Articles Netrin-1 DCC Receptor Axons Cell biology Rats src-Family Kinases chemistry nervous system Tyrosine Guanine nucleotide exchange factor Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Molecular and cellular biology. 33(4) |
| ISSN: | 1098-5549 |
| Popis: | The chemotropic guidance cue netrin-1 mediates attraction of migrating axons during central nervous system development through the receptor Deleted in Colorectal Cancer (DCC). Downstream of netrin-1, activated Rho GTPases Rac1 and Cdc42 induce cytoskeletal rearrangements within the growth cone. The Rho guanine nucleotide exchange factor (GEF) Trio is essential for Rac1 activation downstream of netrin-1/DCC, but the molecular mechanisms governing Trio activity remain elusive. Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr(2622) by the Src kinase Fyn. Though the phospho-null mutant Trio(Y2622F) retained GEF activity toward Rac1, its expression impaired netrin-1-induced Rac1 activation and DCC-mediated neurite outgrowth in N1E-115 neuroblastoma cells. Trio(Y2622F) impaired netrin-1-induced axonal extension in cultured cortical neurons and was unable to colocalize with DCC in growth cones, in contrast to wild-type Trio. Furthermore, depletion of Trio in cortical neurons reduced the level of cell surface DCC in growth cones, which could be restored by expression of wild-type Trio but not Trio(Y2622F). Together, these findings demonstrate that Trio(Y2622) phosphorylation is essential for the regulation of the DCC/Trio signaling complex in cortical neurons during netrin-1-mediated axon outgrowth. |
| Databáze: | OpenAIRE |
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