Phosphorylation of the immunomodulator FTY720 inhibits programmed cell death of fibroblasts via the S1P3 receptor subtype and Bcl-2 activation.

FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inhibiting lymphocyte egress from secondary lymphoid tissues. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate (FTY720-P), which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. Despite its homology to S1P, which exerts antiapoptotic actions in different cells, FTY720 has also been reported to be able to induce apoptosis in a variety of cells. Therefore, we investigated the action of both, FTY720 and its phosphorylated version FTY720-P, on apoptosis. Moreover, signalling pathways of apoptosis in response to FTY720 and FTY720-P were examined. Although FTY720 acts apoptotic at micromolar concentrations in human fibroblasts the phosphorylated compound FTY720-P possesses a pronounced antiapoptotic effect counteracting FTY720-induced programmed cell death. Interestingly, none of the classical antiapoptotic pathways like MAP kinases, Akt or mTOR play a role in the protective role of FTY720-P. Most important, we identified that the S1P(3) receptor subtype is involved in the antiapoptotic action of FTY720-P leading to an increased phosphorylation of Bcl-2 and changes in the mitochondrial membrane potential.

Potteck H ，Nieuwenhuis B ，Lüth A ，van der Giet M ，Kleuser B ... -  《-》

Immunomodulator FTY720 induces myofibroblast differentiation via the lysophospholipid receptor S1P3 and Smad3 signaling.

Keller CD ，Rivera Gil P ，Tölle M ，van der Giet M ，Chun J ，Radeke HH ，Schäfer-Korting M ，Kleuser B ... -  《-》

Production and release of sphingosine 1-phosphate and the phosphorylated form of the immunomodulator FTY720.

Kihara A ，Igarashi Y 《-》

Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2.

Yoshino T ，Tabunoki H ，Sugiyama S ，Ishii K ，Kim SU ，Satoh J ... -  《-》

FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors.

Chiba K 《PHARMACOLOGY & THERAPEUTICS》