Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B.
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.
Tang
Xiaoling
X
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
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
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*
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