Mouse SPNS2 Functions as a Sphingosine-1-Phosphate Transporter in Vascular Endothelial Cells

Abstract

Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1–5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…In addition, S1P could be exported to extracellular environment by the ATP‐binding cassette transporters (ABCA1, ABCC1) 5, 8. Recent studies indicated spinster homolog 2 (Spns2) expressed on endothelial cells (ECs) function as S1P transporter 9, 10. In addition, studies showed that red blood cells and platelets requires the major facilitator superfamily transporter 2b (Mfsd2b) to export S1P 11, 12 and maintained S1P level in blood stream.…”

Fluorescence-based rapid measurement of sphingosine-1-phosphate transport activity in erythrocytes

“…Subsequently, 16 l of 7 M NH 4 OH, 400 l of chloroform, and 300 l of 1.5 M KCl (or distilled water) were extracellular stimuli (13). SPNS2 has been identified as an S1P transporter in vascular and lymphatic endothelial cells (14)(15)(16)(17). A deficiency of SPNS2 in mice decreases the concentration of plasma S1P (14)(15)(16)18) and impairs the egress of lymphocytes from the thymus (14-16, 18, 19).…”

“…SPNS2 has been identified as an S1P transporter in vascular and lymphatic endothelial cells (14)(15)(16)(17). A deficiency of SPNS2 in mice decreases the concentration of plasma S1P (14)(15)(16)18) and impairs the egress of lymphocytes from the thymus (14-16, 18, 19). However, the S1P release from erythrocytes in SPNS2-deficient mice is normal (14).…”

“…A deficiency of SPNS2 in mice decreases the concentration of plasma S1P (14)(15)(16)18) and impairs the egress of lymphocytes from the thymus (14-16, 18, 19). However, the S1P release from erythrocytes in SPNS2-deficient mice is normal (14). Therefore, SPNS2 is not an S1P transporter in erythrocytes, and another unknown transporter must fulfill this role in these cells.…”

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

“…The generation of S1P by SK1 can exert its signaling effects through two routes. In the first, S1P is exported to the outer leaflet via transporter proteins (8,9), where it can act on any of five identified G-protein-coupled receptors (S1P receptors 1-5) (10). Alternatively, S1P is also thought to function as an intracellular signaling molecule acting directly on intracellular targets.…”