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.
Li
Xiaodong
X
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada.
Meriane
Mayya
M
Triki
Ibtissem
I
Shekarabi
Masoud
M
Kennedy
Timothy E
TE
Larose
Louise
L
Lamarche-Vane
Nathalie
N
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D002477:Cells; D015179:Colorectal Neoplasms / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D005810:Multigene Family; D000075386:Netrin Receptors; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology*; D015513:Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000502:physiology; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D000075386:Netrin Receptors; D015513:Oncogene Proteins; D011956:Receptors, Cell Surface; D020830:rac1 GTP-Binding Protein