Sphingosine-1-phosphate (S1P) is a potent lipid mediator that regulates many vital biological processes, including cell growth, death, and differentiation. S1P has been shown to play important roles in normal and patho-physiological processes, including cancer, asthma, allergic responses, hearing, and development of the cardiovascular and nervous systems. In a continuing and highly successful collaboration with Dr. Sarah Spiegel at Virginia Commonwealth University School of Medicine, we are elucidating the mechanisms by which S1P is produced by two sphingosine kinases (SphK1 and SphK2), how its levels are regulated, and how it mediates such diverse actions. S1P is a ligand for five specific G protein-coupled receptors (named S1Psub(1-5)) that regulate many vital cellular processes and account for the pleiotropic effects of S1P. In fact, no cell in the body has been found that does not express as least one S1P receptor. Although they were long considered to be merely structural components of membranes, in the last decades it has become apparent that sphingolipids have other important functions. More recently, S1P and its precursors, sphingosine and ceramide, have been implicated in the regulation of many aspects of neuronal proliferation, differentiation, survival and apoptosis.? We previously found that SphK1 was important for cell growth and survival and SphK2 seemed to inhibit proliferation and promote cell death. SphK1 and SphK2 have different cellular localizations and have opposing roles in the regulation of sphingolipid metabolism suggesting that the location of S1P production in the cell dictates its functions. More recently, we found that ceramide-1-phosphate, produced by phosphorylation of the S1P precursor ceramide by ceramide kinase, a close relative of SphKs, regulates growth and survival of human lung cancer cells and that ceramide kinase expression plays a key role.? In an invited mini-review, we discussed current knowledge of the biochemical properties of this novel family of evolutionarily conserved sphingosine kinases with emphasis on recent studies that have begun to uncover the many biological functions of their phosphorylated sphingoid base products.? We recently examined the regulation of the less well-known SphK isoenzyme, SphK2 and found that epidermal growth factor (EGF), an important growth factor for breast cancer progression, induced its rapid phosphorylation which was markedly reduced by inhibition or downregulation of the MEK1/ERK pathway. ERK1 also was found to be in a complex with SphK2 in vivo. Using site-directed mutagenesis, we showed that SphK2 is phosphorylated on Ser-351 and Thr-578 by ERK1 and that phosphorylation of these residues is required for EGF-stimulated migration of breast cancer cells. This study provided the first clues to the mechanism of agonist-mediated SphK2 activation and enhanced our understanding of the regulation of SphK2 activity by phosphorylation and its role in movement of human breast cancer cells in response to EGF.? In a commentary, we pointed out the importance of the balance between ceramide and S1P in regulation of oxidative stress-mediated cardiac ischemia/reperfusion injury. It has been shown that ceramide mediates cell death in response to reactive oxygen species in a variety of tissues, including liver, brain, and heart, while S1P can protect both cardiac myocytes and isolated hearts from apoptosis. ? Mast cells are tissue-dwelling pivotal early effectors of allergic responses, which produce and secrete S1P, that acts in an autocrine or paracrine manner to influence many facets of the immune system. The relevance of mast cells in the etiology of allergic disorders, asthma and anaphylaxis is well established. We reviewed the contribution of S1P production and secretion to the symptoms associated with dysregulated inflammatory responses and suggested that counteracting the pro-inflammatory effects of S1P might be a therapeutic strategy to treat allergic disorders, asthma, and anaphylactic reactions. In an important paper in PNAS, we showed that S1P is secreted by mast cells through an ABC transporter which has previously been implicated in cancer drug resistance. These findings have important implications for immune responses as well as cancer and other physiological processes in which circulating S1P is important.? Surprisingly, we also found that S1P regulates contraction and tone of detrusor muscle, the smooth muscle that controls bladder function, suggesting that dysregulation of S1P signaling might play a role in overactive bladder syndrome.
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