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https://hdl.handle.net/2440/65122
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Type: | Journal article |
Title: | Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their function |
Author: | Woodcock, J. Ma, Y. Coolen, C. Pham, D. Jones, C. Lopez, A. Pitson, S. |
Citation: | Cellular Signalling, 2010; 22(9):1291-1299 |
Publisher: | Elsevier Science Inc |
Issue Date: | 2010 |
ISSN: | 0898-6568 1873-3913 |
Statement of Responsibility: | Joanna M. Woodcock, Yuefang Ma, Carl Coolen, Duyen Pham, Claire Jones, Angel F. Lopez, Stuart M. Pitson |
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. |
Keywords: | Sphingosine 14-3-3 protein Apoptosis FTY720 |
Rights: | © 2010 Elsevier Inc. All rights reserved. |
DOI: | 10.1016/j.cellsig.2010.04.004 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.1016/j.cellsig.2010.04.004 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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