Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their function.
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.
Woodcock
Joanna M
JM
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, SA 5000, Australia. Joanna.Woodcock@health.sa.gov.au
Ma
Yuefang
Y
Coolen
Carl
C
Pham
Duyen
D
Jones
Claire
C
Lopez
Angel F
AF
Pitson
Stuart M
SM
D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002522:Chlorocebus aethiops; D000068876:Fingolimod Hydrochloride; D006801:Humans; D019169:Jurkat Cells; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011409:Propylene Glycols / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000099157:Sphingosine Kinase
D048948:14-3-3 Proteins; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D020033:Protein Isoforms; D051745:Protein Kinase C-delta; D013110:Sphingosine; D000099157:Sphingosine Kinase; C061800:N,N-dimethylsphingosine