An autocrine sphingosine-1-phosphate signaling loop enhances NF-kappaB-activation and survival.
BACKGROUND
Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates a multitude of cellular functions, including cell proliferation, survival, migration and angiogenesis. S1P mediates its effects either by signaling through G protein-coupled receptors (GPCRs) or through an intracellular mode of action. In this study, we have investigated the mechanism behind S1P-induced survival signalling.


RESULTS
We found that S1P protected cells from FasL-induced cell death in an NF-kappaB dependent manner. NF-kappaB was activated by extracellular S1P via S1P2 receptors and Gi protein signaling. Our study also demonstrates that extracellular S1P stimulates cells to rapidly produce and secrete additional S1P, which can further amplify the NF-kappaB activation.


CONCLUSIONS
We propose a self-amplifying loop of autocrine S1P with capacity to enhance cell survival. The mechanism provides increased understanding of the multifaceted roles of S1P in regulating cell fate during normal development and carcinogenesis.
Blom
Tomas
T
Department of Biology, Abo Akademi University, 20520 Turku, Finland.
Bergelin
Nina
N
Meinander
Annika
A
Löf
Christoffer
C
Slotte
J Peter
JP
Eriksson
John E
JE
Törnquist
Kid
K
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D053222:Fas Ligand Protein / Q000378:metabolism; D025461:Feedback, Physiological; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D053222:Fas Ligand Protein; D005419:Flavonoids; C471998:JTE 013; D008246:Lysophospholipids; D016328:NF-kappa B; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; C466999:SPHKAP protein, human; C060506:sphingosine 1-phosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013110:Sphingosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one