Sphingosine-1-phosphate: From insipid lipid to a key regulator
2020; Elsevier BV; Volume: 295; Issue: 10 Linguagem: Inglês
10.1074/jbc.x120.012838
ISSN1083-351X
Autores Tópico(s)Lysosomal Storage Disorders Research
ResumoIt is a great honor to be asked to write a "Reflections" article by one of the true icons of biochemistry, Herb Tabor. I felt humbled, especially since it follows many written by biochemists I admire and whose contributions have shaped major advances in biochemistry and molecular biology in the last century. Here I present my personal reflections on my adventure with the bioactive sphingolipid metabolite sphingosine-1-phosphate intertwined with those of my family life as a wife, mother, and grandmother. These reflections brought back many memories of events in my early career that played significant roles in determining the path I have taken for more than 40 years and that brought much fun and satisfaction into my life. It has been an exciting journey so far, with many surprises along the way, that still continues. It is a great honor to be asked to write a "Reflections" article by one of the true icons of biochemistry, Herb Tabor. I felt humbled, especially since it follows many written by biochemists I admire and whose contributions have shaped major advances in biochemistry and molecular biology in the last century. Here I present my personal reflections on my adventure with the bioactive sphingolipid metabolite sphingosine-1-phosphate intertwined with those of my family life as a wife, mother, and grandmother. These reflections brought back many memories of events in my early career that played significant roles in determining the path I have taken for more than 40 years and that brought much fun and satisfaction into my life. It has been an exciting journey so far, with many surprises along the way, that still continues. I was born in a small town in Israel near Tel Aviv called Holon that in Hebrew means "little sand." The sand dunes that Holon was built on are now gone, and it has become a large urban city. My parents, Lea and Baruch Arazi, raised me in a wonderful, loving home with an amazing older brother, Yossi, who adored me. I was always a very good student and loved math and science but had very little patience for any subject that required memorization. Throughout my childhood, I remember my big brother keeping me out of mischief and inspiring me to try to be as kind a human being as he was. He also saved our house from bursting into flames one day due to a fire I started with an unsupervised chemistry set experiment. So, although from an early age I hoped to become a scientist, these initial "experiments" did nothing to suggest that I would have a future as a chemist. In high school, I chose the math/science concentration, partly because of the very small class size with a 3:1 ratio of boys to girls. Although we had a lot of fun in class and after school, our curriculum was very rigorous to prepare us for admission to university. I was more interested in mathematics and physics than chemistry or biology, but we had an excellent chemistry teacher who went far beyond the traditional curriculum and encouraged us to carry out independent science projects. By this time, my science projects no longer ended up in flames and even received first-place awards. Although army service in Israel is mandatory for 18-year-olds, because of eye problems, I was not allowed to serve. Thus, when I was admitted to Hebrew University in Jerusalem and enrolled as an undergraduate student with a major in chemistry, I was much younger than the rest of the students. I was a bit intimidated by the prospect of competing with more mature students but quickly realized that being younger was not a major disadvantage. I tremendously enjoyed classes in physics and chemistry in my first year. But there was a black cloud on the horizon. During that summer, I had a retinal detachment and after surgery spent the next two vacation months in the hospital with friends and family reading Agatha Christie mysteries to me. If not for the encouragement of my eye doctor, I might have given up on my studies. When I took organic chemistry and physical organic chemistry, I was hooked. As the curriculum was not too demanding for me, I had time to carry out a research project in Professor Zvi Rappoport's lab characterizing mechanisms important for chemical reactions and identifying reactive intermediates. Graduation, summa cum laude with a degree in chemistry, was followed by the one of the most important events in my life, the birth of my daughter Shlomit, whose name means peace in Hebrew. I sometimes joked with friends that this stimulated the peace agreement between Israel and Egypt two years later. It also changed my perspective on science, and my interests shifted from theoretical physical organic chemistry to more biological and health-related research. The usual path to the Ph.D. in Israel is through the M.S. degree. Nevertheless, an outstanding GPA allows one to apply for the direct path to the Ph.D. I decided to apply to the Feinberg Graduate School at the Weizmann Institute of Science, the leading research institute in Israel. I interviewed with several distinguished professors there but was most impressed with Professor Meir Wilchek from the Biophysics Department. He was one of the superstars at the Weizmann who, while a visiting scientist at the National Institutes of Health (NIH), pioneered the development of affinity chromatography for protein purification and the avidin-biotin system, which still today have major impacts on biomedical research. To combine my interests and Meir's expertise in organic chemistry and affinity labeling, my thesis project was designed to chemically modify sialic acid residues on the surface of lymphocytes with radioactive N,4-dinitrophenyl-l-2,4-diaminobutyric acid hydrazide (DNP-DABH). 2The abbreviations used are: DNP-DABHN,4-dinitrophenyl-l-2,4-diaminobutyric acid hydrazideCTcholera toxinPKCprotein kinase CS1Psphingosine-1-phosphateS1PRssphingosine-1-phosphate receptorsSphKsphingosine kinasePDGFplatelet-derived growth factorGPCRG protein–coupled receptorLPAlysophosphatidic acidABCATP-binding cassetteHDAChistone deacetylase. This labeled both glycoproteins and glycolipids with concomitant preservation of the mitogenic activity induced by cross-linking with anti-DNP antibody. To our surprise, I found that the major difference between stimulated committed and noncommitted DNP-modified lymphocytes is the amount of ligand attached to the cell-surface sialoglycolipids (gangliosides) rather than sialo-glycoproteins. This finding was not well-received by the members of the Biophysics Department, whose major research interest was glycoproteins and lectins that bind to their sugars. However, Meir was extremely supportive and was sure that we had discovered something very important (Fig. 1A). Indeed, my first paper describing the involvement of gangliosides in lymphocyte stimulation was published in the Proceedings of the National Academy of Sciences (1Spiegel S. Ravid A. Wilchek M. Involvement of gangliosides in lymphocyte stimulation.Proc. Natl. Acad. Sci. U.S.A. 1979; 76 (116227): 5277-528110.1073/pnas.76.10.5277Crossref PubMed Scopus (43) Google Scholar). Over the years, Meir often reminded me that this paper was also the first description of lipid capping, even before the introduction of the concept of lipid rafts. Meir's advice that I should always follow my gut feelings has carried me throughout my career. N,4-dinitrophenyl-l-2,4-diaminobutyric acid hydrazide cholera toxin protein kinase C sphingosine-1-phosphate sphingosine-1-phosphate receptors sphingosine kinase platelet-derived growth factor G protein–coupled receptor lysophosphatidic acid ATP-binding cassette histone deacetylase. Meir's lab was a wonderful place to learn, and he was a great role model. He usually came to the laboratory early in the morning and washed the dirty "dishes" from our previous day's organic reactions. Embarrassed by seeing the famous professor doing this menial chore, I finally got the courage to ask him whether I could do this instead of him. He politely refused and with a small grin explained that his best research ideas emerged when he was washing dishes. For years, I tried to imitate him, but I am still waiting for my own eureka moments while doing housework. As my graduate work had sparked a strong interest on gangliosides and glycosphingolipids, I spent a lot of time reading about their structures and functions. I vividly remember spending hours in the library competing with other students for access to the single printed copy of the Journal of Biological Chemistry, which was delivered by mail at least two months later than it was available in the United States. I started to write my thesis on the involvement of gangliosides in lymphocyte stimulation while on maternity leave with my son Michael, who brought additional light into my life, and he gave me inspiration and courage to seriously pursue a scientific career. As a single parent in graduate school, spending long hours in the laboratory was not always easy. I will always be very thankful and indebted to my parents, Baruch and Lea Arazi, who were just a phone call away whenever I needed their help. I was planning on doing a postdoctoral fellowship in the U.S. but the children were too young, so I stayed for another year at the Weizmann and continued working with Meir. I also initiated collaborative studies with Dr. Joseph (Yossi) Schlessinger, who pioneered the method of fluorescent photobleaching recovery measurement. We showed that the inserted fluorescent gangliosides that I prepared were free to diffuse in the plane of the membrane with diffusion coefficients much higher than those of proteins (2Spiegel S. Schlessinger J. Fishman P.H. Incorporation of fluorescent gangliosides into human fibroblasts: mobility, fate, and interaction with fibronectin.J. Cell Biol. 1984; 99 (6430916): 699-70410.1083/jcb.99.2.699Crossref PubMed Scopus (50) Google Scholar). Yossi, whose interests were in receptor tyrosine kinases for which he is very well-known and received numerous awards, used to kid me about wasting time on the little guys (sphingolipids) rather than on big guys (receptors) in membranes. I hope that, by now, even he appreciates their important biological functions. It was 1982 when I received the Dr. Chaim Weizmann Post-Doctoral Fellowship for Scientific Research, and the time was right for packing up my two kids and going abroad for postdoctoral research training (Fig. 1B). This prestigious postdoctoral fellowship award enabled me to overcome the challenges of relocating to a foreign country, living on a single parent's salary, and uprooting my young children. I decided to work with Dr. Peter Fishman, whose research was focused on gangliosides in Dr. Roscoe Brady's branch. Roscoe was already world-renowned for pioneering work on biochemistry and the enzymatic basis of inherited defects in sphingolipid metabolism. Although the Fishman lab was small, around six people, there were many investigators in the Developmental and Metabolic Neurology Branch who shared my interest in understanding the biosynthesis and functions of gangliosides and other glycosphingolipids. Most of the clinicians set out to find the underlying defects in the devastating hereditary metabolic storage diseases called lipid or lysosomal storage disorders that include the sphingolipidoses. This line of research ultimately led to their development of successful enzyme-replacement therapies (3Barton N.W. Furbish F.S. Murray G.J. Garfield M. Brady R.O. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease.Proc. Natl. Acad. Sci. U.S.A. 1990; 87 (2308952): 1913-191610.1073/pnas.87.5.1913Crossref PubMed Scopus (329) Google Scholar). I was more attracted to understanding ganglioside roles in cellular recognition, cell communication, and regulation of biological processes. The NIH was an exciting, stimulating research environment full of bright, interesting people who were eager to collaborate. The presence of experienced investigators was especially helpful for me to become resourceful and independent. I was fortunate to be able to collaborate with several well-known cell biology investigators, such as Drs. Joel Moss and Ken Yamada. Together, we used the fluorescent gangliosides that I developed previously at the Weizmann Institute (1Spiegel S. Ravid A. Wilchek M. Involvement of gangliosides in lymphocyte stimulation.Proc. Natl. Acad. Sci. U.S.A. 1979; 76 (116227): 5277-528110.1073/pnas.76.10.5277Crossref PubMed Scopus (43) Google Scholar, 4Spiegel S. Kassis S. Wilchek M. Fishman P.H. Direct visualization of redistribution and capping of fluorescent gangliosides on lymphocytes.J. Cell Biol. 1984; 99 (6436251): 1575-158110.1083/jcb.99.5.1575Crossref PubMed Scopus (74) Google Scholar) as probes to study organization of fibronectin in ganglioside-deficient cells (5Spiegel S. Yamada K.M. Hom B.E. Moss J. Fishman P.H. Fluorescent gangliosides as probes for the retention and organization of fibronectin by ganglioside-deficient mouse cells.J. Cell Biol. 1985; 100 (3882721): 721-72610.1083/jcb.100.3.721Crossref PubMed Scopus (35) Google Scholar, 6Spiegel S. Yamada K.M. Hom B.E. Moss J. Fishman P.H. Fibrillar organization of fibronectin is expressed coordinately with cell surface gangliosides in a variant murine fibroblast.J. Cell Biol. 1986; 102 (3700477): 1898-190610.1083/jcb.102.5.1898Crossref PubMed Scopus (34) Google Scholar). We introduced a new idea that gangliosides can mediate the attachment of fibronectin to the cell surface and its organization into a fibrillar network (5Spiegel S. Yamada K.M. Hom B.E. Moss J. Fishman P.H. Fluorescent gangliosides as probes for the retention and organization of fibronectin by ganglioside-deficient mouse cells.J. Cell Biol. 1985; 100 (3882721): 721-72610.1083/jcb.100.3.721Crossref PubMed Scopus (35) Google Scholar). We also showed that the ability of a cell to organize fibronectin into an extracellular matrix depended on specific gangliosides, yet cell adhesion to fibronectin was independent (6Spiegel S. Yamada K.M. Hom B.E. Moss J. Fishman P.H. Fibrillar organization of fibronectin is expressed coordinately with cell surface gangliosides in a variant murine fibroblast.J. Cell Biol. 1986; 102 (3700477): 1898-190610.1083/jcb.102.5.1898Crossref PubMed Scopus (34) Google Scholar). This work was the first to suggest that matrix organization and cell attachment and spreading are based on separate mechanisms and that these functions are associated with different cell-surface receptors. Postdoctoral fellowships at NIH usually last for two years. Since my research was taking off, Peter suggested at the end of my second year that I should stay at NIH for an additional year as a visiting associate. This opened a new chapter in my life, as I met and married my sweetheart, Dr. Sheldon Milstien, who was a senior scientist at NIH, and decided to continue my career in the U.S. Shel has been a loyal, loving best friend who enriched my life immensely and was a partner in raising a wonderful family. A major interest of the Fishman laboratory at that time was cholera toxin (CT), the causative agent of the diarrheal disease cholera. Although its structure was not yet known, it was accepted that CT was composed of an A subunit and a homopentameric B subunit with different functions. Peter's goal was to understand how the A subunit ADP-ribosylates and activates the Gs protein, leading to increased adenylate cyclase activity and cAMP and its role in toxin actions (7Rebois R.V. Beckner S.K. Brady R.O. Fishman P.H. Mechanism of action of glycopeptide hormones and cholera toxin: what is the role of ADP-ribosylation?.Proc. Natl. Acad. Sci. U.S.A. 1983; 80 (6572387): 1275-127910.1073/pnas.80.5.1275Crossref PubMed Scopus (14) Google Scholar). I, on the other hand, was fascinated by the observation that the pentameric B submit binds to ganglioside GM1. Together, we made an important discovery (published in Science (8Spiegel S. Fishman P.H. Weber R.J. Direct evidence that endogenous ganglioside GM1 can mediate thymocyte proliferation.Science. 1985; 230 (2999979): 1285-128710.1126/science.2999979Crossref PubMed Scopus (86) Google Scholar)) that the B subunit, which is multivalent and binds exclusively to five molecules of ganglioside GM1, was mitogenic for lymphocytes. Mitogenesis depended on the direct interaction of the B subunit with GM1 on the surface of the cells. This was the first demonstration that endogenous plasma membrane ganglioside GM1 in lipid microdomains can transmit a signal across the plasma membrane to induce cell proliferation (8Spiegel S. Fishman P.H. Weber R.J. Direct evidence that endogenous ganglioside GM1 can mediate thymocyte proliferation.Science. 1985; 230 (2999979): 1285-128710.1126/science.2999979Crossref PubMed Scopus (86) Google Scholar). The B subunit of CT labeled with a fluorescent tag is still used to identify lipid microdomains/lipid rafts. We later observed that the B subunit inhibits the growth of Ras-transformed fibroblasts, whereas untransformed cells exhibit opposing responses to the B subunit, depending on their state of growth (9Spiegel S. Fishman P.H. Gangliosides as bimodal regulators of cell growth.Proc. Natl. Acad. Sci. U.S.A. 1987; 84 (3540954): 141-14510.1073/pnas.84.1.141Crossref PubMed Scopus (129) Google Scholar). We concluded that endogenous gangliosides may be bimodal regulators of signals of cell growth and raised the possibility that other physiological processes could also be triggered by interactions with gangliosides on the cell surface. Despite all of these studies, I still did not understand then how the signal could be transduced from the outer leaflet of the plasma membrane, where gangliosides reside, across the cytoplasm to the nucleus to regulate DNA synthesis and proliferation (10Dixon S.J. Stewart D. Grinstein S. Spiegel S. Transmembrane signaling by the B subunit of cholera toxin: increased cytoplasmic free calcium in rat lymphocytes.J. Cell Biol. 1987; 105 (3654749): 1153-116110.1083/jcb.105.3.1153Crossref PubMed Scopus (83) Google Scholar, 11Spiegel S. Inhibition of protein kinase C-dependent cellular proliferation by interaction of endogenous ganglioside GM1 with the B subunit of cholera toxin.J. Biol. Chem. 1989; 264 (2674135): 16512-16517Abstract Full Text PDF PubMed Google Scholar, 12Spiegel S. Possible involvement of a GTP-binding protein in a late event during endogenous ganglioside-modulated cellular proliferation.J. Biol. Chem. 1989; 264 (2496120): 6766-6772Abstract Full Text PDF PubMed Google Scholar). Luckily, the Department of Biochemistry and Molecular Biology at Georgetown University Medical School had an opening, and I decided, as a new assistant professor, to tackle this intriguing puzzle (13Buckley N.E. Matyas G.R. Spiegel S. The bimodal response of Swiss 3T3 cells to the B subunit of cholera toxin is independent of the density of its receptor, ganglioside GM1.Exp. Cell Res. 1990; 189 (2347373): 13-2110.1016/0014-4827(90)90250-ECrossref PubMed Scopus (25) Google Scholar, 14Spiegel S. Cautionary note on the use of the B subunit of cholera toxin as a ganglioside GM1 probe: detection of cholera toxin A subunit in B subunit preparations by a sensitive adenylate cyclase assay.J. Cell Biochem. 1990; 42 (2156874): 143-15210.1002/jcb.240420305Crossref PubMed Scopus (19) Google Scholar). Since I had received my first grant, the start-up source had disappeared into thin air. Instead, I got some old equipment from retired faculty, and my daughter Shlomit helped me set up my first small lab of 400 square feet. With help from students and Shel, we painted the whole lab a nice clean white. I was fascinated by the idea raised by Drs. Robert M. Bell and Yusuf Hannun that the sphingolipid metabolite sphingosine might be a direct inhibitor of protein kinase C (PKC) (15Hannun Y.A. Bell R.M. Functions of sphingolipid and sphingolipid breakdown products in cellular regulation.Science. 1989; 243 (2643164): 500-50710.1126/science.2643164Crossref PubMed Scopus (1094) Google Scholar), a key enzyme in signaling that was known then to play a critical role in cell growth regulation. They proposed that in addition to the well-known lipid signaling molecule diacylglycerol, which is derived from metabolism of glycerolphospholipids and stimulates PKC, sphingolipid metabolism produces the bioactive metabolite sphingosine that inhibits it. However, with one of my first rotation students, we surprisingly found that sphingosine stimulates rather than inhibits cell proliferation. Our results unexpectedly demonstrated that sphingosine acts as a positive regulator of cell growth in a fundamentally different, PKC-independent pathway (16Zhang H. Buckley N.E. Gibson K. Spiegel S. Sphingosine stimulates cellular proliferation via a protein kinase C-independent pathway.J. Biol. Chem. 1990; 265 (2294122): 76-81Abstract Full Text PDF PubMed Google Scholar, 17Zhang H. Desai N.N. Murphey J.M. Spiegel S. Increases in phosphatidic acid levels accompany sphingosine-stimulated proliferation of quiescent Swiss 3T3 cells.J. Biol. Chem. 1990; 265 (2250025): 21309-21316Abstract Full Text PDF PubMed Google Scholar). Obviously, the "big guys" in the field did not readily accept this idea, and it took some time before Al Merrill and Yusuf Hannun became my best colleague friends. Ignoring criticisms, and with the conviction that we were on the right track, we next set out to determine how sphingosine affects cell growth. In fact, we observed that it is not sphingosine itself, but, rather, it becomes rapidly converted to a unique phospholipid. Before the era of mass spectrometry (MS), thin-layer chromatography (TLC) was the main method used to separate and identify lipids. Two-dimensional TLC analysis revealed that sphingosine induces the formation of an unidentified 32P-labeled phospholipid spot that did not co-migrate with any of the known phospholipids. After much effort, we showed that this mystery compound, which I originally nicknamed "schmutz" (Yiddish for dirt), is sphingosine-1-phosphate (S1P) (18Zhang H. Desai N.N. Olivera A. Seki T. Brooker G. Spiegel S. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation.J. Cell Biol. 1991; 114 (2050740): 155-16710.1083/jcb.114.1.155Crossref PubMed Scopus (547) Google Scholar). It was then that my career began to take off, suggesting that sometimes gold can be found even in a dirt pile (Fig. 2A). We found that S1P is produced from sphingosine by an uncharacterized sphingosine kinase (SphK) and has much higher potency than sphingosine itself as a mitogen and in mobilization of calcium from internal stores (18Zhang H. Desai N.N. Olivera A. Seki T. Brooker G. Spiegel S. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation.J. Cell Biol. 1991; 114 (2050740): 155-16710.1083/jcb.114.1.155Crossref PubMed Scopus (547) Google Scholar). Thus, a tantalizing link between sphingolipid metabolism and cellular proliferation emerged from our discovery that the sphingolipid metabolite S1P is not only a component of the final degradative step in the metabolism of all sphingolipids, as was shown by Professor Stoffel in the early 1970s (19Stoffel W. Assmann G. Binczek E. Metabolism of sphingosine bases. XIII. Enzymatic synthesis of 1-phosphate esters of 4t-sphingenine (sphingosine), sphinganine (dihydrosphingosine), 4-hydroxysphinganine (phytosphingosine) and 3-dehydrosphingosine by erythrocytes.Hoppe-Seylers Z. Physiol. Chem. 1970; 351 (4315749): 635-64210.1515/bchm2.1970.351.1.635Crossref PubMed Scopus (55) Google Scholar, 20Stoffel W. Assmann G. Metabolism of sphingoid bases, XV. Enzymatic degradation of 4t-sphigenine 1-phosphate (sphingosine-1-phosphate) to 2t-hexadecen-1-al and ethanolamine phosphate.Hoppe-Seylers Z. Physiol. Chem. 1970; 351 (4317971): 1041-104910.1515/bchm2.1970.351.2.1041Crossref PubMed Scopus (50) Google Scholar), but is also a novel bioactive sphingolipid that regulates cellular proliferation (18Zhang H. Desai N.N. Olivera A. Seki T. Brooker G. Spiegel S. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation.J. Cell Biol. 1991; 114 (2050740): 155-16710.1083/jcb.114.1.155Crossref PubMed Scopus (547) Google Scholar, 21Desai N.N. Zhang H. Olivera A. Mattie M.E. Spiegel S. Sphingosine-1-phosphate, a metabolite of sphingosine, increases phosphatidic acid levels by phospholipase D activation.J. Biol. Chem. 1992; 267 (1429659): 23122-23128Abstract Full Text PDF PubMed Google Scholar). This early study on S1P was well-received by the glycosphingolipid community, and Professor Hakomori, the guru of glycosphingolipids, invited me in 1991 to present a plenary lecture at the 11th International Symposium on Glycoconjugates (Fig. 3). Intriguingly, sphingosine was named by Thudichum in 1884 after the Greek mythological creature the Sphinx because of its enigmatic nature (22Thudichum J.L.W. A Treatise on the Chemical Constitution of Brain. Bailliere, Tindall, and Cox, London1884Google Scholar). More than a century later, we are just beginning to unravel the S1P riddle. I have been fortunate to attract many outstanding postdoctoral fellows to my lab over the years, beginning with the talented Dr. Ana Olivera from Spain, who later became my lifelong colleague and dear friend. Ana found that potent mitogens, like platelet-derived growth factor (PDGF), stimulate SphK, leading to S1P formation. When SphK activity is inhibited, not only do S1P levels become reduced, but, importantly, DNA synthesis induced by PDGF is greatly suppressed (23Olivera A. Spiegel S. Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens.Nature. 1993; 365 (8413613): 557-56010.1038/365557a0Crossref PubMed Scopus (802) Google Scholar). Our report in Nature on this provided the first clue to a missing link between the plasma membrane (where growth factor receptors are found) and cellular proliferation, namely S1P. We suggested that S1P has properties that make it a suitable candidate to function as a messenger in this link: It elicits diverse cellular responses; its turnover is rapid; its level in cells is low and increases transiently in response to growth factors; and it releases calcium from internal stores independently of inositol trisphosphate. This was the first suggestion that activation of SphK and S1P production play important roles in signal transduction pathways triggered by growth factors (23Olivera A. Spiegel S. Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens.Nature. 1993; 365 (8413613): 557-56010.1038/365557a0Crossref PubMed Scopus (802) Google Scholar). My journey to understanding the paradigm that sphingolipid metabolites serve as signaling molecules, particularly S1P, which is now the most thoroughly characterized mediator in this field, was recognized in 2009 by the ASBMB Avanti Award in Lipids (Fig. 4). In 1995, I was nominated to organize the Glycolipid and Sphingolipid Biology Gordon Conference. I was flattered since I was among the youngest in the group, and Professor Sen-itiroh Hakomori, who nominated me, was one of my idols. I enthusiastically embraced this task. In organizing this conference, I hoped to increase participation of female scientists and the focus on bioactive sphingolipid metabolites. It was a great honor for me to organize this and many other GRC and FASEB meetings, and it has been very satisfying to see how the field has grown and changed over the past 20 years, especially the large increase in female participation (see the 1998 and 2014 GRC meetings in Ventura in Fig. 5). In the early 1990s, several laboratories, particularly those of Drs. Yusuf Hannun and Richard Kolesnick, showed that another sphingolipid metabolite, ceramide, the backbone of all sphingolipids and a precursor of S1P, is an important regulatory component of apoptosis and cell growth arrest induced by stress stimuli and cytokines. Two of my postdoctoral fellows, Olivier Cuvillier from France and Burkhard Kleuser from Germany, were fascinated by those studies. Together with Dr. Silvio Gutkind at NIH, we showed that inhibition of ceramide-mediated apoptosis by activation of PKC results from stimulation of SphK and the concomitant increase in S1P (24Cuvillier O. Pirianov G. Kleuser B. Vanek P.G. Coso O.A. Gutkind S. Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.Nature. 1996; 381 (8657285): 800-80310.1038/381800a0Crossref PubMed Scopus (1311) Google Scholar). This led us to suggest the concept of a "sphingolipid rheostat" in which the dynamic balance between these counteracting sphingolipid metabolites and consequent regulation of different family members of mitogen-activated protein kinases are major determinants of cell fate. In other words, elevation of ceramide signals cell death, whereas S1P elevation signals cell growth and survival (24Cuvillier O. Pirianov G. Kleuser B. Vanek P.G. Coso O.A. Gutkind S. Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.Nature. 1996; 381 (8657285): 800-80310.1038/381800a0Crossref PubMed Scopus (1311) Google Scholar). Since then, many reports have substantiated the importance of the sphingolipid rheostat in cell-fate determination in health and diseases. Moreover, modulation of the rheostat has emerged as a focal point for treatment strategies to battle cancer. The aforementioned results also implicate SphK as a key regulator of the "rheostat" (24Cuvillier O. Pirianov G. Kleuser B. Vanek P.G. Coso O.A. Gutkind S. Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.Nature. 1996; 381 (8657285): 800-80310.1038/381800a0Crossref PubMed Scopus (1311) Google Scholar, 25Edsall L.C. Pirianov G.G. Spiegel S. Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and dif
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