title: UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE.
abstract: The UNC5Hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis. Here, we report an interaction between UNC5H1 and NRAGE. Our experiments show that this interaction is responsible for apoptosis induced by UNC5H1, and this level of apoptosis is greater than the amount induced by either UNC5H2 or UNC5H3. We mapped the NRAGE binding domain of UNC5H1 to its ZU-5 domain and show that this region, in addition to an adjacent PEST sequence, is required for UNC5H1-mediated apoptosis. Chimeric UNC5H2 and UNC5H3 receptors, containing the NRAGE binding domain and PEST sequence of UNC5H1, bind NRAGE and cause increased levels of apoptosis. UNC5H1 expression does not induce apoptosis in differentiated PC12 cells, which down-regulate NRAGE, but induces apoptosis in native PC12 cells that endogenously express high levels of NRAGE and in differentiated PC12 cells when NRAGE is overexpressed. Together, these results demonstrate a mechanism for UNC5H1-mediated apoptosis that requires an interaction with the MAGE protein NRAGE.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Williams
authors.forename: Phyllis
authors.initials: P
authors.lastname: Strickland
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000502:physiology*; D051379:Mice; D009363:Neoplasm Proteins; D000075386:Netrin Receptors; D009474:Neurons / Q000473:pathology / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C486541:Maged1 protein, mouse; C486542:Maged1 protein, rat; C000617308:Unc5A protein, mouse; C000617307:Unc5b protein, mouse