title: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tang
authors.forename: Sung-Wuk
authors.initials: SW
authors.lastname: Jang
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.forename: Chi-Bun
authors.initials: CB
authors.lastname: Chan
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Luo
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rama
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D014443:Tyrosine / Q000737:chemistry; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617308:Unc5A protein, mouse; C572338:Unc5d protein, mouse; D000075388:Netrin-1; D014443:Tyrosine; D051076:Proto-Oncogene Proteins c-fyn; C485997:AGAP2 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C529781:PIKE protein, mouse; D018631:ras Proteins