FOR MORE THAN A CENTURY FOLLOWING the discovery of sphingolipids, biochemists viewed these ubiquitous phospholipids as pharmacologically silent structural elements of the cell membrane. After the identification of G protein-coupled receptors for sphingosine-1-phosphate (S1P) (1, 8, 10), researchers began to recognize the importance of sphingolipid-mediated cell signaling, and this recognition l...

Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressi...

The sphingosine 1-phosphate receptor 1 (S1P(1)) promotes lymphocyte egress from lymphoid organs. Previous work showed that agonist-induced internalization of this G protein-coupled receptor correlates with inhibition of lymphocyte egress and results in lymphopenia. However, it is unclear if S1P(1) internalization is necessary for this effect. We characterize a knockin mouse (S1p1r(S5A/S5A)) in ...

Akt plays a pivotal role in cell survival and tumorigenesis. We investigated the potential interaction between sphingosine-1-phosphate (S1P) and platelet-derived growth factor (PDGF) in the Akt signaling pathway. Using mouse embryonic fibroblasts (MEFs) from S1P receptor knockout mice, we show here that S1P3 was required for S473 phosphorylation of Akt by S1P. In addition, S1P-stimulated activa...

Mast cells play a central role in inflammatory and immediate-type allergic reactions by secreting a variety of biologically active substances, including sphingosine-1 phosphate (S1P). Sphingosine kinase 1 (SphK1) and formation of S1P, which leads to transactivation of S1P receptors and their downstream signaling pathways, regulates mast-cell functions initiated by cross-linking of the high-affi...

Lymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P(1)), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P(1) receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and...

The vascular and immune systems of mammals are closely intertwined: the individual components of the immune system must move between various body compartments to perform their function effectively. Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, exerts effects on the two organ systems and influences the interaction between them. In the resting state, the vascular S1P gradient contrib...

Sphingosine-1-phosphate regulates diverse biological processes through five receptor types, S1P(1-5). Two or more S1P receptors are usually co-expressed on target cells. We have previously shown that smooth muscle cells of the gut co-express S1P(1) and S1P(2) receptors that could mediate distinct functions. In the absence of selective agonists and antagonists, we developed siRNA constructs to s...

The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway, known to determine the fate and growth of various cell types, can enhance cardiac myocyte survival in vitro and provide cardioprotection in acute ex vivo heart preparations. However, the relevance of these findings to chronic cardiac pathology has never been demonstrated. We hypothesized that S1P signaling is impaired during c...

In vascular endothelial cells, specialized microdomains of plasma membrane termed caveolae modulate various receptor signal transduction pathways regulated by caveolin-1, a resident protein of caveolae. We examined whether transforming growth factor-beta1 (TGF-beta1), a multifunctional cytokine, alters expression levels of caveolin-1 and influences heterologous receptor signaling. Treatment of ...