Letter abstract
Nature Cell Biology 10, 698 - 706 (2008)
Published online: 11 May 2008 | doi:10.1038/ncb1732
Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B
Xiaoling Tang1,5, Sung-Wuk Jang1,5, Masashi Okada1, Chi-Bun Chan1, Yue Feng2, Yu Liu3, Shi-Wen Luo3, Yan Hong3, Nicolas Rama4, Wen-Cheng Xiong3, Patrick Mehlen4 & Keqiang Ye1
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.
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
- Institute of Molecular Medicine & Genomics and Department of Neurology, Medical College of Georgia, Augusta, GA 30809, USA.
- Apoptose, Cancer et Développement, CNRS UMR5238, University of Lyon, Centre Léon Bérard, Équipe 'La Ligue', 28 rue Laennec, 69008 Lyon, France.
- These authors contributed equally to this work.
Correspondence to: Keqiang Ye1 e-mail: kye@emory.edu
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