"Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets

Abstract

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody.

Fig. 1

“Inside-out” signaling of S1P. The scheme depicts the metabolism and actions of S1P in broad strokes. S1P is produced by phosphorylation of sphingosine by sphingosine kinases, emerging chemotherapeutic targets. Several lines of evidence suggest that S1P can act intracellularly on as yet unknown targets. S1P can also be exported from cells via ABC transporters and act on cell surface S1P receptors in autocrine or paracrine manners. This extracellular S1P has been targeted by a monoclonal antibody (sphingomab) to block its proliferative and angiogenic effects. In addition, a therapeutic agent directed toward S1P₁, FTY720 (fingolimod), is currently being developed for treatment of MS. The flags, labeled Fig. 2, Fig. 3, Fig. 4, and Fig. 5, indicate the portion that is shown in more detail in the respective figures.

Fig. 2

Structures and formation of interconvertible bioactive sphingolipid metabolites. The relative concentrations of the bioactive sphingolipid metabolites, S1P, sphingosine, and ceramide represent a rheostat that determines cell fate. S1P is antiapoptotic and progrowth, whereas its precursors, sphingosine and ceramide are proapoptotic and antiproliferative.

Fig. 3

S1P receptors and the major downstream biological processes that they regulate. S1P receptors have been implicated in the regulation of a wide variety of cellular and biological processes including lymphocyte trafficking, cell migration, angiogenesis, neurogenesis, and others.

Fig. 4

Export of S1P and neutralization with a monoclonal antibody. S1P is produced inside cells by sphingosine kinases and can be exported by ABC transporters. After externalization, a newly developing monoclonal antibody directed toward S1P (sphingomab) can bind and sequester S1P, thereby preventing its interaction with S1P receptors and its angiogenic/proliferative effects.

Fig. 5

Internalization of S1P₁ by FTY720 after phosphorylation by SphK2. FTY720 (fingolimod) is a sphingosine analog, which, after phosphorylation by SphK2, acts as a “super” agonist of S1P₁, leading to sustained S1P₁ receptor internalization and lymphocyte sequestration.