Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their function.

Abstract

The dimeric 14-3-3 protein family protects cells from apoptosis by regulating pro-apoptotic molecules. Conversely, the cationic lipid sphingosine is associated with physiological apoptosis and induces apoptosis in its own right by a largely undefined mechanism. We show here that sphingosine and 14-3-3 interact directly in the control of cell death. The binding of sphingosine to 14-3-3 proteins renders them phosphorylatable at the dimer interface, an event that abolishes the pro-survival signalling of 14-3-3. Sphingosine kinase 1 reduces availability of sphingosine for interaction with 14-3-3, thus inhibiting cell death and providing a new mechanistic insight into the role of this enzyme in cell survival and oncogenesis. Importantly, FTY720, a sphingosine analogue with apoptotic activity that is currently in phase III clinical trials for multiple sclerosis, acts in a similar manner to sphingosine in potentiating 14-3-3 phosphorylation. The biological significance of 14-3-3 phosphorylation was demonstrated with a non-phosphorylatable 14-3-3zeta mutant which retarded apoptosis induced by sphingosine and FTY720. These results demonstrate that direct association of sphingosine with 14-3-3 is required for 14-3-3 phosphorylation, and that this axis can control cell fate. Furthermore, these results suggest a new therapeutic activity for FTY720 as an anti-cancer agent based on this mechanism.

• Authors: Joanna M Woodcock, Yuefang Ma, Carl Coolen, Duyen Pham, Claire Jones, Angel F Lopez, Stuart M Pitson
• Journal: Cellular signalling (Cell Signal) Vol. 22 Issue 9 Pg. 1291-9 (Sep 2010) ISSN: 1873-3913 [Electronic] England
• PMID: 20403428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• 14-3-3 Proteins
• Propylene Glycols
• Protein Isoforms
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Protein Kinase C-delta
• Caspases
• Fingolimod Hydrochloride
• N,N-dimethylsphingosine
• Sphingosine

Topics

• 14-3-3 Proteins (metabolism)
• Animals
• Apoptosis
• COS Cells
• Caspases (metabolism)
• Cell Survival
• Chlorocebus aethiops
• Fingolimod Hydrochloride
• Humans
• Jurkat Cells
• Phosphorylation
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)
• Propylene Glycols (metabolism, pharmacology)
• Protein Isoforms (metabolism)
• Protein Kinase C-delta (metabolism)
• Sphingosine (analogs & derivatives, metabolism, pharmacology)