The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2

@article{Paugh2003TheIF,
  title={The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2},
  author={Steven W. Paugh and Shawn G. Payne and Suzanne E. Barbour and Sheldon Milstien and Sarah Spiegel},
  journal={FEBS Letters},
  year={2003},
  volume={554}
}

Sphingosine Kinase 2 Is Required for Modulation of Lymphocyte Traffic by FTY720*

Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases.

Phosphorylation by Sphingosine Kinase 2 is Essential for in vivo Potency of FTY720 Analogues

The synthesis and systematic investigation of FTY720-like amino alcohols featuring two stereocenters in the head group are reported in order to establish the relative importance of SPHK phosphorylation compared with potency toward S1P1 for lymphopenia induction in vivo.

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720*

The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720.

This work demonstrates that human SPNS2 can transport several S1P analogues, including FTY720-P, and identifies the first identification of an FTY 720-P transporter in cells.

Sphingosine 1-phosphate receptor type 1 as a novel target for the therapy of autoimmune diseases

FTY720 inhibits S1P1-dependent lymphocyte egress from SLO to decrease circulation of lymphocytes including autoreactive T cells and shows immunomodulating effects on autoimmune disease models.

Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate.

A cationic amphiphilic small molecule is reported that is a selective SphK2 inhibitor that characterizes this compound in wild-type and SphK-null mice and finds that administration of the inhibitor resulted in a rapid increase in blood S1P, which is in contrast with the authors' SphK1 inhibitor that drives circulating S 1P levels down.

Effects of Synthetic Pseudoceramides on Sphingosine Kinase Activity in F9-12 Cells

A simple SPHK assay system was developed to find SPHK regulatory pseudoceramide compounds, K10 PC-5 and K6PC-5 which may be useful to cancer treatment or immune regulation like FTY720, a synthetic sphingolipid mimetic compound.

Discovery of fingolimod, the sphingosine 1-phosphate receptor modulator and its application for the therapy of multiple sclerosis.

Fingolimod (FTY720) is a first-in-class, orally active, sphingosine 1-phosphate (S1P)-receptor modulator with a structure closely related to sphingosine. The compound was discovered by chemical
...

References

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The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors*

The results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.

Sphingosine Kinase Type 2 Is a Putative BH3-only Protein That Induces Apoptosis*

SphK2 enhanced apoptosis in diverse cell types and also suppressed cellular proliferation, and the apoptotic effect of SphK2 might be because of its putative BH3 domain.

FTY720: A new kid on the block for transplant immunosuppression

  • F. AkiB. Kahan
  • Biology, Medicine
    Expert opinion on biological therapy
  • 2003
Since FTY720 seems to spare nonspecific elements of host resistance, it may address the not infrequent complications of infections associated with existing therapies, and suggest several potential advantages: it does not produce hyperlipidaemia, diabetes mellitus, nephrotoxicity, neurotoxicity or myelosuppression, which are characteristic of other immunosuppressants.

Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists

It is shown that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolites of the immunosuppressive agent FTY720.

Molecular Cloning and Functional Characterization of a Novel Mammalian Sphingosine Kinase Type 2 Isoform*

Northern blot analysis revealed that SPHK2 mRNA expression had a strikingly different tissue distribution from that of SPHK1 and appeared later in embryonic development, and is another member of a growing class of sphingolipid kinases that may have novel functions.

Molecular Cloning and Functional Characterization of Murine Sphingosine Kinase*

The data suggest that sphingosine kinase is a prototypical member of a new class of lipid kinases, and an important step in corroborating the intracellular role of SPP as a second messenger.

Purification and Characterization of Rat Kidney Sphingosine Kinase*

Purified sphingosine kinase has an apparent molecular mass of ∼49 kDa under denaturing conditions on SDS-polyacrylamide gel, which is similar to the molecular mass determined by gel filtration, suggesting that the active form is a monomer.

Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus.

FTY720 suppressed the development of autoimmunity and prolonged the lifespan of female MRL/lpr mice and could be useful for primary or adjunctive therapy of human SLE.