The adaptor protein Nck-1 couples the netrin-1 receptor DCC (deleted in colorectal cancer) to the activation of the small GTPase Rac1 through an atypical mechanism.
Netrins are a family of secreted proteins that guide the migration of cells and axonal growth cones during development. DCC (deleted in colorectal cancer) is a receptor for netrin-1 implicated in mediating these responses. Here, we show that DCC interacts constitutively with the SH3/SH2 adaptor Nck in commissural neurons. This ... interaction is direct and requires the SH3 but not SH2 domains of Nck-1. Moreover, both DCC and Nck-1 associate with the actin cytoskeleton, and this association is mediated by DCC. A dominant negative Nck-1 inhibits the ability of DCC to induce neurite outgrowth in N1E-115 cells and to activate Rac1 in fibroblasts in response to netrin-1. These studies provide evidence for an important role of mammalian Nck-1 in a novel signaling pathway from an extracellular guidance cue to changes in the actin-based cytoskeleton responsible for axonal guidance.
Mesh Terms:
3T3 Cells, Adaptor Proteins, Signal Transducing, Animals, Animals, Newborn, Cells, Colorectal Neoplasms, Gene Deletion, Humans, Mice, Multigene Family, Neuroblastoma, Neurons, Oncogene Proteins, Rats, Receptor Cross-Talk, Receptors, Cell Surface, Spinal Cord, Tumor Cells, Cultured, rac1 GTP-Binding Protein, src Homology Domains
3T3 Cells, Adaptor Proteins, Signal Transducing, Animals, Animals, Newborn, Cells, Colorectal Neoplasms, Gene Deletion, Humans, Mice, Multigene Family, Neuroblastoma, Neurons, Oncogene Proteins, Rats, Receptor Cross-Talk, Receptors, Cell Surface, Spinal Cord, Tumor Cells, Cultured, rac1 GTP-Binding Protein, src Homology Domains
J. Biol. Chem.
Date: Oct. 04, 2002
PubMed ID: 12149262
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