Akt and 14-3-3 Control a PACS-2 Homeostatic Switch that Integrates Membrane Traffic with TRAIL-Induced Apoptosis

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, require...

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Published in:	Molecular cell Vol. 34; no. 4; pp. 497 - 509
Main Authors:	Aslan, Joseph E., You, Huihong, Williamson, Danielle M., Endig, Jessica, Youker, Robert T., Thomas, Laurel, Shu, Hongjun, Du, Yuhong, Milewski, Robert L., Brush, Matthew H., Possemato, Anthony, Sprott, Kam, Fu, Haian, Greis, Kenneth D., Runckel, Douglas N., Vogel, Arndt, Thomas, Gary
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 14-05-2009
Subjects:	14-3-3 Proteins - genetics 14-3-3 Proteins - metabolism Animals Apoptosis - physiology BH3 Interacting Domain Death Agonist Protein - genetics BH3 Interacting Domain Death Agonist Protein - metabolism Caspases - metabolism Cell Line, Tumor Cell Membrane - metabolism CELLBIO CELLCYCLE Cells, Cultured Fibroblasts - cytology Fibroblasts - metabolism Homeostasis Humans Mice Mice, Knockout Neoplasms - metabolism Neoplasms - pathology PROTEINS Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Serine - metabolism TNF-Related Apoptosis-Inducing Ligand - genetics TNF-Related Apoptosis-Inducing Ligand - metabolism Vesicular Transport Proteins - genetics Vesicular Transport Proteins - metabolism CELLBIO PROTEINS CELLCYCLE
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors contributed equally to this work
ISSN:	1097-2765 1097-4164
DOI:	10.1016/j.molcel.2009.04.011