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

被引：58

作者：

Aslan, Joseph E. ^{[1
]}

You, Huihong ^{[1
]}

Williamson, Danielle M. ^{[1
]}

Endig, Jessica ^{[2
]}

Youker, Robert T. ^{[1
]}

Thomas, Laurel ^{[1
]}

Shu, Hongjun ^{[3
]}

Du, Yuhong ^{[4
,5
]}

Milewski, Robert L. ^{[6
]}

Brush, Matthew H. ^{[1
]}

Possemato, Anthony ^{[7
]}

Sprott, Kam ^{[7
]}

Fu, Haian ^{[4
,5
]}

Greis, Kenneth D. ^{[3
]}

Runckel, Douglas N. ^{[6
]}

Vogel, Arndt ^{[2
]}

Thomas, Gary ^{[1
]}

机构：

[1] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA

[2] Hannover Med Sch, Clin Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany

[3] Univ Cincinnati, Genome Res Inst, Cincinnati, OH 45237 USA

[4] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA

[5] Emory Univ, Sch Med, Emory Chem Biol Discovery Ctr, Atlanta, GA 30322 USA

[6] Kaiser Permanente, Portland, OR 97230 USA

[7] Cell Signaling Technol, Danvers, MA 01923 USA

来源：

MOLECULAR CELL | 2009年 / 34卷 / 04期

基金：

美国国家卫生研究院;

关键词：

CELL-LINE LNCAP; PROSTATE-CANCER; DOWN-REGULATION; PATHWAY; SURVIVAL; DEATH; ACTIVATION; RESISTANCE; CARCINOMA; CASPASE-8;

D O I：

10.1016/j.molcel.2009.04.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：497 / 509

页数：13

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