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

Nature Cell Biology volume 10, pages 698–706 (2008)Cite this article

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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References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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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Author notes

  1. Xiaoling Tang and Sung-Wuk Jang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Xiaoling Tang, Sung-Wuk Jang, Masashi Okada, Chi-Bun Chan & Keqiang Ye

  2. Department of Pharmacology, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Yue Feng

  3. Institute of Molecular Medicine & Genomics and Department of Neurology, Medical College of Georgia, Augusta, 30809, GA, USA

    Yu Liu, Shi-Wen Luo, Yan Hong & Wen-Cheng Xiong

  4. Apoptose, Cancer et Développement, CNRS UMR5238, University of Lyon, Centre Léon Bérard, Équipe 'La Ligue', 28 rue Laennec, 69008, Lyon, France

    Nicolas Rama & Patrick Mehlen

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Contributions

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, SW., 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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