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

doi:10.1016/j.molcel.2009.04.011

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

Research output: Contribution to journal › Article › peer-review

60 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 language	English (US)
Pages (from-to)	497-509
Number of pages	13
Journal	Molecular Cell
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2009.04.011
State	Published - May 14 2009

Keywords

CELLBIO
CELLCYCLE
PROTEINS

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2009.04.011

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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

Aslan, JE, You, H, Williamson, DM, Endig, J, Youker, RT, Thomas, L, Shu, H, Du, Y, Milewski, RL, Brush, MH, Possemato, A, Sprott, K, Fu, H, Greis, KD, Runckel, DN, 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, vol. 34, no. 4, pp. 497-509. https://doi.org/10.1016/j.molcel.2009.04.011

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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.",

keywords = "CELLBIO, CELLCYCLE, PROTEINS",

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

note = "Funding Information: The authors thank N. Hay, T. Soderling, R. Cone, A. Aitken, P. Rotwein, G. Thomas, S. Somlo, H. Piwnica-Worms, M. Iordanov, A. Guo, and B. Vogelstein for reagents; S. Nath and K. Benson for experiments in the early stages of this project; and B. Druker and G. Thomas for critical reading of the manuscript. H.F. is a Georgia Cancer Coalition Distinguished Cancer Scholar and a Georgia Research Alliance Distinguished Investigator. This work was supported by Deutsche Krebshilfe (A.V.) and by National Institutes of Health (NIH) grants T32 AI07472 (J.E.A.); T32 DK007680 (M.H.B.); NRSA DK076343 (R.T.Y.); P01CA116676 and P50CA128613 (H.F. and Y.D.); and DK3724, AI49793, P50CA97186, and OCTRI RR0241 (G.T.). ",

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doi = "10.1016/j.molcel.2009.04.011",

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T1 - Akt and 14-3-3 Control a PACS-2 Homeostatic Switch that Integrates Membrane Traffic with TRAIL-Induced Apoptosis

AU - Aslan, Joseph E.

AU - You, Huihong

AU - Williamson, Danielle M.

AU - Endig, Jessica

AU - Youker, Robert T.

AU - Thomas, Laurel

AU - Shu, Hongjun

AU - Du, Yuhong

AU - Milewski, Robert L.

AU - Brush, Matthew H.

AU - Possemato, Anthony

AU - Sprott, Kam

AU - Fu, Haian

AU - Greis, Kenneth D.

AU - Runckel, Douglas N.

AU - Vogel, Arndt

AU - Thomas, Gary

N1 - Funding Information: The authors thank N. Hay, T. Soderling, R. Cone, A. Aitken, P. Rotwein, G. Thomas, S. Somlo, H. Piwnica-Worms, M. Iordanov, A. Guo, and B. Vogelstein for reagents; S. Nath and K. Benson for experiments in the early stages of this project; and B. Druker and G. Thomas for critical reading of the manuscript. H.F. is a Georgia Cancer Coalition Distinguished Cancer Scholar and a Georgia Research Alliance Distinguished Investigator. This work was supported by Deutsche Krebshilfe (A.V.) and by National Institutes of Health (NIH) grants T32 AI07472 (J.E.A.); T32 DK007680 (M.H.B.); NRSA DK076343 (R.T.Y.); P01CA116676 and P50CA128613 (H.F. and Y.D.); and DK3724, AI49793, P50CA97186, and OCTRI RR0241 (G.T.).

PY - 2009/5/14

Y1 - 2009/5/14

N2 - 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.

AB - 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.

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KW - CELLCYCLE

KW - PROTEINS

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U2 - 10.1016/j.molcel.2009.04.011

DO - 10.1016/j.molcel.2009.04.011

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AN - SCOPUS:65849216826

SN - 1097-2765

VL - 34

SP - 497

EP - 509

JO - Molecular Cell

JF - Molecular Cell

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ER -

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

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