Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis.
Mol Cell
; 34(4): 497-509, 2009 May 14.
Article
em En
| MEDLINE
| ID: mdl-19481529
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Membrana Celular
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Apoptose
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Proteínas de Transporte Vesicular
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Proteínas 14-3-3
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Proteínas Proto-Oncogênicas c-akt
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Ligante Indutor de Apoptose Relacionado a TNF
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Homeostase
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article