title: Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis.
abstract: TRAIL selectively kills diseased cells in vivo, spurring interest in this death ligand as a potential therapeutic. However, many cancer cells are resistant to TRAIL, suggesting the mechanism mediating TRAIL-induced apoptosis is complex. Here we identify PACS-2 as an essential TRAIL effector, required for killing tumor cells in vitro and virally infected hepatocytes in vivo. PACS-2 is phosphorylated at Ser437 in vivo, and pharmacologic and genetic studies demonstrate Akt is an in vivo Ser437 kinase. Akt cooperates with 14-3-3 to regulate the homeostatic and apoptotic properties of PACS-2 that mediate TRAIL action. Phosphorylated Ser437 binds 14-3-3 with high affinity, which represses PACS-2 apoptotic activity and is required for PACS-2 to mediate trafficking of membrane cargo. TRAIL triggers dephosphorylation of Ser437, reprogramming PACS-2 to promote apoptosis. Together, these studies identify the phosphorylation state of PACS-2 Ser437 as a molecular switch that integrates cellular homeostasis with TRAIL-induced apoptosis.
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Aslan
authors.forename: Huihong
authors.initials: H
authors.lastname: You
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Williamson
authors.forename: Jessica
authors.initials: J
authors.lastname: Endig
authors.forename: Robert T
authors.initials: RT
authors.lastname: Youker
authors.forename: Laurel
authors.initials: L
authors.lastname: Thomas
authors.forename: Hongjun
authors.initials: H
authors.lastname: Shu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Robert L
authors.initials: RL
authors.lastname: Milewski
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Brush
authors.forename: Anthony
authors.initials: A
authors.lastname: Possemato
authors.forename: Kam
authors.initials: K
authors.lastname: Sprott
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Greis
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Runckel
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C529570:Pacs2 protein, mouse; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D033921:Vesicular Transport Proteins; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases