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.
Supplementary Figures S1, S2, S3, S4, S5, S6 (PDF 1179 kb)
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