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

Xiaoling Tang, Sung Wuk Jang, Masashi Okada, Chi Bun Chan, Yue Feng, Yu Liu, Shi Wen Luo, Yan Hong, Nicolas Rama, Wen Cheng Xiong, Patrick Mehlen, Keqiang Ye

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Netrins, a family of secreted molecules, have critical functions in axon guidance and cell migration during neuronal development. In addition to its role as a chemotropic molecule, netrin-1 also acts as a survival factor. 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 apoptosis. 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.

Original languageEnglish (US)
Pages (from-to)698-706
Number of pages9
JournalNature Cell Biology
Volume10
Issue number6
DOIs
StatePublished - Jun 2008

ASJC Scopus subject areas

  • Cell Biology

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    Tang, X., Jang, S. W., Okada, M., Chan, C. B., Feng, Y., Liu, Y., Luo, S. W., Hong, Y., Rama, N., Xiong, W. C., Mehlen, P., & Ye, K. (2008). Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. Nature Cell Biology, 10(6), 698-706. https://doi.org/10.1038/ncb1732