Netrins, a family of secreted molecules, have critical functions in axon guidance and cell migration during neuronal development1,2. In addition to its role as a chemotropic molecule, netrin-1 also acts as a survival factor3,4,5,6,7. Both UNC5 (that is, UNC5A, UNC5B, UNC5C or UNC5D) and DCC are transmembrane receptors for netrin-1 (Refs 8, 9). In the absence of netrin-1, DCC and UNC5 act as dependence receptors and trigger apoptosis3,6,10. However, how netrin-1 suppresses the apoptotic activity of the receptors remains elusive. Here we show that netrin-1 induces interaction of UNC5B with the brain-specific GTPase PIKE-L. This interaction triggers the activation of PtdIns-3-OH kinase signalling, prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. Moreover, this process relies strongly on Fyn because PIKE-L is tyrosine phosphorylated in response to netrin-1, and the netrin-1-mediated interaction of UNC5B with PIKE-L is inhibited in Fyn-null mice. Thus, PIKE-L acts as a downstream survival effector for netrin-1 through UNC5B in the nervous system.
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This work is supported by a grant from the National Institutes of Health (RO1, NS045627) to K.Y. and by grants from ANR and Ligue Contre le Cancer to P.M.
The authors declare no competing financial interests.
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Tang, X., Jang, S., Okada, M. et al. Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. Nat Cell Biol 10, 698–706 (2008). https://doi.org/10.1038/ncb1732
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