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

Joseph E. Aslan, Huihong You, Danielle M. Williamson, Jessica Endig, Robert T. Youker, Laurel Thomas, Hongjun Shu, Yuhong Du, Robert L. Milewski, Matthew H. Brush, Anthony Possemato, Kam Sprott, Haian Fu, Kenneth D. Greis, Douglas N. Runckel, Arndt Vogel, Gary Thomas

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44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)497-509
Number of pages13
JournalMolecular Cell
Volume34
Issue number4
DOIs
StatePublished - May 14 2009

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Keywords

  • CELLBIO
  • CELLCYCLE
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Aslan, J. E., You, H., Williamson, D. M., Endig, J., Youker, R. T., Thomas, L., Shu, H., Du, Y., Milewski, R. L., Brush, M. H., Possemato, A., Sprott, K., Fu, H., Greis, K. D., Runckel, D. N., Vogel, A., & Thomas, G. (2009). Akt and 14-3-3 Control a PACS-2 Homeostatic Switch that Integrates Membrane Traffic with TRAIL-Induced Apoptosis. Molecular Cell, 34(4), 497-509. https://doi.org/10.1016/j.molcel.2009.04.011