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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 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.

SUBMITTER: Tang X 

PROVIDER: S-EPMC2839190 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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

Tang Xiaoling X   Jang Sung-Wuk SW   Okada Masashi M   Chan Chi-Bun CB   Feng Yue Y   Liu Yu Y   Luo Shi-Wen SW   Hong Yan Y   Rama Nicolas N   Xiong Wen-Cheng WC   Mehlen Patrick P   Ye Keqiang K  

Nature cell biology 20080511 6


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 r  ...[more]

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