Figure 2.

S1P axis modulators and their effects on S1P signaling.

Notes: (A) S1PR1 is activated by its natural ligand, S1P, resulting in the activation of its G-coupled protein Gαi. FTY720, KRP-203, and W-061 are all superagonists of S1PR1 with functional antagonist activity leading to the desensitization and internalization of S1PR1, thus attenuating S1P-associated signaling through this receptor. Note that FTY720 also acts on S1PR3–5, KRP-203 has a slight agonist activity on S1PR4, and W-061 also acts on S1PR4–5. (B) Sphingosine kinases produce S1P from sphingosine. ABC747080, ABC294640, and FTY720 are sphingosine kinase inhibitors that either block SK activity or, in the case of FTY720, cause proteasomal degradation of the kinases. ABC747080 and FTY720 are SphK1 inhibitors and ABC294640 inhibits Sphk2.

Abbreviations: S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor; ER, endoplasmic reticulum; SphK, sphingosine kinase.