Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in cell proliferation angiogenesis inflammation and malignant transformation among additional functions. nervous MC1568 metabolic cardiovascular musculoskeletal and renal systems. This review also identifies the role of this receptor in tumor growth and metastasis and suggests potential restorative avenues that exploit S1PR2. synthesis of ceramide which is considered to be a central component of sphingolipid rate of metabolism. Complex sphingolipids such as sphingomyelin and glycosphingolipids are generated from ceramide [5] MC1568 which can be cleaved to form sphingo-sine or phosphorylated yielding cIAP2 ceramide 1-phosphate. Sphingosine can also be phosphorylated to form S1P probably one of the most analyzed sphingolipids due to its bioactive tasks in cellular biology and physiology (cellular proliferation swelling migration and angiogenesis). Intracellular and extracellular S1P are under limited control by several enzymes. Specifically hydrolysis of complex sphingolipids is definitely controlled by sphingomyelinases and glycosidases. Subsequently ceramidases can hydrolyze ceramide to produce sphingosine a direct precursor of S1P from the action of sphingosine kinases [6]. S1P is also controlled by enzymes responsible for its degradation (S1P phosphatases and S1P MC1568 lyase). The biological tasks of S1P are mediated either directly by intracellular focuses on [7] or from the action of five different transmembrane G protein coupled receptors (S1PR1-5) [8] which MC1568 belong to the endothelial differentiation gene (EDG) family of receptors. S1P receptors participate in cellular reactions based on the cell type and downstream available effectors. Figure 1 gives a depiction of the sphingolipid metabolic pathway. Fig. 1 (A) Schematic representation of the sphingolipids metabolic pathway. (B) The different biological functions downstream of S1PR2. With this review the practical tasks of S1P receptors are explained prefaced with a brief history of their finding. S1PR1 and S1PR3 have been extensively stud ied and is only discussed briefly here. S1PR4 and S1PR5 which are less well characterized are discussed more comprehensively. The main focus of this review is within the S1PR2 receptor: specifically its normal physiological functions and its part in pathophysiology and disease. Issues and apparent controversies surrounding the S1PR2 receptor will also be discussed. S1P transporters Before delving into S1PR activation an understanding is needed of how S1P relocates to the cell outside to activate its receptors in an autocrine or paracrine manner. Unlike sphingosine S1P cannot freely traverse the lipid bilayer to leave the cell [1]. Its polar nature prevents this; therefore it requires a specific transport mechanism. To day two mechanisms have been proposed for S1P transport out of the cell. First several members of the ATP-binding cassette family of transporters have been thought to participate in this translocation [9 10 Cystic fibrosis transmembrane receptor has been implicated in S1P transport as well as lysophosphatidic acid and dihydro-S1P in C127/cystic fibrosis trans-membrane receptor cells [10]. ABCC1 however has been explained in mast cells and its inhibition affected the migratory capabilities of mast cells during swelling [9]. The second mechanism proposed is definitely through the newly recognized spinster-2 transporter in vascular endothelial cells. Mice lacking this protein possess 60% less circulating S1P and they have defective lymphocyte egress [11]. S1P receptors Before 1995 S1P-mediated actions on cellular processes MC1568 such as proliferation cell movement and intra-cellular calcium levels were thought to be primarily related to its intracellular second messenger effects. Also during that yr – and thereafter -evidence accumulated that this sphingolipid functions on G protein-coupled receptors. Goodemote dramatically inhibited tumor growth of implanted Lewis lung carcinoma cells by inhibiting fresh blood vessel formation within the growing tumor mass [30]. S1PR3 Studies that address the practical capabilities of S1PR3 only have been historically scarce; only now is MC1568 study becoming reported about this receptor. Several published observations suggest that S1PR3-mediated functions happen in coordination with S1PR1 or S1PR2..