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


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.


  1. 1

    Keino-Masu, K. et al. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell 87, 175–185 (1996).

  2. 2

    Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996).

  3. 3

    Mehlen, P. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998).

  4. 4

    Thiebault, K. et al. The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment. Proc. Natl Acad. Sci. USA 100, 4173–4178 (2003).

  5. 5

    Llambi, F., Causeret, F., Bloch-Gallego, E. & Mehlen, P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J. 20, 2715–2722 (2001).

  6. 6

    Tanikawa, C., Matsuda, K., Fukuda, S., Nakamura, Y. & Arakawa, H. p53RDL1 regulates p53-dependent apoptosis. Nature Cell Biol. 5, 216–223 (2003).

  7. 7

    Llambi, F. et al. The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase. EMBO J. 24, 1192–1201 (2005).

  8. 8

    Ackerman, S. L. et al. The mouse rostral cerebellar malformation gene encodes an UNC-5-like protein. Nature 386, 838–842 (1997).

  9. 9

    Leonardo, E. D. et al. Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386, 833–838 (1997).

  10. 10

    Williams, M. E., Strickland, P., Watanabe, K. & Hinck, L. UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE. J. Biol. Chem. 278, 17483–17490 (2003).

  11. 11

    Ye, K. et al. Pike. A nuclear GTPase that enhances PI3kinase activity and is regulated by protein 4.1N. Cell 103, 919–930 (2000).

  12. 12

    Ye, K. et al. Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature 415, 541–544 (2002).

  13. 13

    Rong, R. et al. PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nature Neurosci. 6, 1153–1161 (2003).

  14. 14

    Tang, X., Feng, Y. & Ye, K. Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival. Cell Death Differ. 14, 368–377 (2007).

  15. 15

    Li, W. et al. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nature Neurosci. 7, 1213–1221 (2004).

  16. 16

    Liu, G. et al. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Nature Neurosci. 7, 1222–1232 (2004).

  17. 17

    Ren, X. R. et al. Focal adhesion kinase in netrin-1 signaling. Nature Neurosci. 7, 1204–1212 (2004).

  18. 18

    Meriane, M. et al. Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance. J. Cell Biol. 167, 687–698 (2004).

  19. 19

    Chang, C. et al. MIG-10/lamellipodin and AGE-1/PI3K promote axon guidance and outgrowth in response to slit and netrin. Curr. Biol. 16, 854–862 (2006).

  20. 20

    Campbell, D. S. & Holt, C. E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32, 1013–1026 (2001).

  21. 21

    Ming, G. et al. Phospholipase C-γ and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron 23, 139–148 (1999).

  22. 22

    Schauwecker, P. E. & Steward, O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc. Natl Acad. Sci. USA 94, 4103–4108 (1997).

  23. 23

    Lu, X. et al. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179–186 (2004).

  24. 24

    Xie, Y. et al. DCC-dependent phospholipase C signaling in netrin-1-induced neurite elongation. J. Biol. Chem. 281, 2605–2611 (2006).

  25. 25

    Hong, K. et al. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97, 927–941 (1999).

  26. 26

    Williams, M. E. et al. UNC5A promotes neuronal apoptosis during spinal cord development independent of netrin-1. Nature Neurosci. 9, 996–998 (2006).

  27. 27

    Williams, M. E., Wu, S. C., McKenna, W. L. & Hinck, L. Surface expression of the netrin receptor UNC5H1 is regulated through a protein kinase C-interacting protein/protein kinase-dependent mechanism. J. Neurosci. 23, 11279–11288 (2003).

  28. 28

    Tang, X. et al. Sperm membrane protein (hSMP-1) and RanBPM complex in the microtubule-organizing centre. J. Mol. Med. 82, 383–388 (2004).

  29. 29

    Tang, X. & Ye, K. Pike tyrosine phosphorylation regulates its apoptotic cleavage during programmed cell death. Adv. Enzyme Regul. 46, 289–300 (2006).

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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.

Author information

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.

Correspondence to Keqiang Ye.

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