Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B

Abstract

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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Figure 1: PIKE-L interacts with UNC5B.
Figure 2: Netrin-1 mediates the interaction between PIKE-L and UNC5B through tyrosine phosphorylation.
Figure 3: Interaction of PIKE-L and UNC5B is regulated by Fyn tyrosine kinase.
Figure 4: PIKE-L and Fyn are necessary for netrin-1-triggered PI(3)K activation.
Figure 5: PIKE-L and Fyn are essential for the neuronal survival effect induced by netrin-1.

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Acknowledgements

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.

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X.T., S.-W.J., M.O., C.-B.C., Y.L., S.-W. L., Y.H. and N.R. performed the experimental work and data analysis; Y.F. provided reagents; W.-C.X., P.M. and K.Y. planned the project and wrote the manuscript.

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Correspondence to Keqiang Ye.

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The authors declare no competing financial interests.

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

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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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