Sphingosine-1-phosphate regulation of mammalian development

Abstract

Sphingosine-1-phosphate (S1P) was first identified as a lysophospholipid metabolite whose formation is required for the irreversible degradation of sphingolipids. Years later, it was discovered that S1P is a bioactive lipid that provokes varied cell responses by acting through cell-surface receptors to drive cell signaling. More recent findings in model organisms have now established that S1P metabolism and signaling are integrated into many physiological systems. We describe here the surprising breadth of function of S1P in mammalian development and the underlying biologic processes that S1P regulates.

Figure 1

S1P metabolism and receptor signaling. De novo sphingolipid metabolism begins in the endoplasmic reticulum (ER) with the condensation of palmitoyl-CoA and serine to produce 3-ketosphinganine (3-KS). Next, conversion to dihydrosphingosine (DH-Sph) occurs, followed by acylation to form dihydroceramide (DH-Cer). Ceramide (Cer) is derived by desaturation and is transported to the Golgi for conversion to sphingomyelin (SM). Ceramide, generated either from the de novo pathway or from degradation of plasma membrane sphingolipids such as sphingomyelin, is deacylated to yield sphingosine (Sph), which is phosphorylated by sphingosine kinases 1 and 2 (Sphk1, 2) to produce S1P. S1P can be secreted from cells (dashed line) and can stimulate one of the members of the S1P receptor family (S1P_1–5), which transmit signals through heterotrimeric G proteins. In addition, S1P and dihydroS1P (DH-S1P), from the phosphorylation of dihydrosphingosine, can be degraded to yield ethanolamine phosphate (Eth-P), which is utilized for phosphatidylethanolamine (PE) synthesis.

Figure 2

Role of S1P and its receptors in mammalian development. S1P and S1P receptors are essential for embryonic vascular and nervous system development. During pregnancy, maternal S1P synthesis, mediated by sphingosine kinases 1 and 2 (Sphk1, 2), is also essential for embryonic development. Possible underlying biologic roles of S1P are indicated in the boxes.