Netrins are a family of secreted molecules that are important for axonal outgrowth and guidance in the developing nervous system. However, the signaling mechanisms that lie immediately downstream of netrin receptors remain poorly understood. Here we report that the netrin receptor DCC (deleted in colorectal cancer) interacts with the focal adhesion kinase (FAK), a kinase implicated in regulating cell adhesion and migration. FAK was expressed in developing brains and was localized with DCC in cultured neurons. Netrin-1 induced FAK and DCC tyrosine phosphorylation. Disruption of FAK signaling abolished netrin-1-induced neurite outgrowth and attractive growth cone turning. Taken together, these results indicate a new signaling mechanism for DCC, in which FAK is activated upon netrin-1 stimulation and mediates netrin-1 function; they also identify a critical role for FAK in axon navigation.
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We are grateful to Y. Rao (Washington University), D. Ilic (University of California at San Francisco) and B. Vogelstein (Johns Hopkins Medical School) for reagents. We thank L. Xu (University of Alabama at Birmingham) for help on statistical analyses. G.L.M. is partially supported by Charles E. Culpeper Scholarships in Medical Science and the National Institutes of Health (NIH). This study is supported by grants from the NIH to Z.F.C., L.M., and W.C.X.
The authors declare no competing financial interests.
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Ren, Xr., Ming, Gl., Xie, Y. et al. Focal adhesion kinase in netrin-1 signaling. Nat Neurosci 7, 1204–1212 (2004). https://doi.org/10.1038/nn1330
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