Chair, Professor of Biochemistry & Molecular Biology
PO Box 980614
Richmond, VA 23298-0614
Email: sspiegel@vcu.edu
Telephone: 804-828-6971
Education
Ph.D., The Weizmann Institute of Science, Israel, 1983, Biochemistry
Post-Doc
- 1983-1984: Dr. Chaim Weizmann Post-doctoral Fellowship for Scientific Research
- 1985-1986: Visiting Associate, Membrane Biochemistry Section,
Developmental and Metabolic Neurology Branch, NINCDS, NIH, Bethesda, Maryland
Research
Sphingosine-1-Phosphate: New Player in Cell Growth, Apoptosis, Tumor Angiogenesis, and Immune Responses
Research in our laboratory is focused on the enigmatic lipid mediator,
sphingosine-1-phosphate (S1P) whose role in cell growth regulation was
discovered in my lab more than a decade ago (Nature 365: 557, 1993). Our studies
have shown that in contrast to its precursors, sphingosine and ceramide, which
have been implicated in programmed cell death (apoptosis), S1P suppresses
apoptosis. Thus, we proposed that the dynamic balance between levels of S1P and
ceramide/sphingosine determines whether a cell survives or dies (Nature, 381:
800, 1996). More recently, there has been an explosion of important
physiological and pathophysiological processes, including cancer, vascular
maturation, angiogenesis, cardiac development, atherosclerosis, immunity and
asthma, that are reported to be regulated by S1P in higher organisms. S1P has
also been detected in plants, worms, flies, slime mould and yeast, and also
regulates important biological responses even in these lower organisms, further
highlighting its importance as a signaling molecule. The puzzle of how such a
simple molecule as S1P can have such diverse roles has been resolved by our
discovery that it belongs to a class of lipid mediators that function not only
inside cells but also as ligands (agonists) for five specific cell-surface
receptors (Nature Rev. Mol. Cell Biol. 4: 397, 2003). Our goal is to elucidate
the molecular mechanisms of action of this potent lipid mediator and its
cross-talk with known intracellular signal transduction pathways using
biochemical, chemical, molecular, and cellular approaches. We also have cloned
and characterized sphingosine kinases and S1P phosphatases that control levels
of S1P to use as molecular tools to unravel its molecular mechanisms of action.
This should provide important clues to the understanding of the unrestrained
proliferation of cancer cells, neurodegenerative and cardiovascular diseases,
infertility, and asthma, disorders in which S1P plays an important role, and
also help to create novel therapeutics targeted specifically to sphingolipid
signaling pathways.
Highlights of Current Findings
We discovered that transactivation of S1P receptors by receptor tyrosine
kinases, such as the PDGF receptor, is important for cytoskeleton
rearrangements and directed cell movement (Science 291: 1800, 2001). This
study not only provided a new mechanistic concept for cross communication
between tyrosine kinase receptors and GPCRs but also underscored the
importance of S1P in vascular maturation and blood vessel formation.
Surprisingly, we recently found that this "S1P axis" also plays an
important role in asthma and neuronal differentiation and we are now
investigating the mechanisms of its effects in these processes.
Mast cells secrete various substances that initiate and perpetuate
allergic responses. We recently showed that cross-linking of the
high-affinity receptor for IgE (FcepsilonRI) of mast cells activates
sphingosine kinase, which leads to generation and secretion of S1P.
Subsequent transactivation of S1P receptors is required for mast cell
degranulation and chemotaxis, important events in inflammation and asthma
and might be involved in the movement of mast cells to sites of
inflammation.
Since sphingosine kinase, the enzyme that produces S1P, stimulates
growth and suppresses apoptosis and S1P is important for vascular
maturation, angiogenesis, cancer, asthma, and neuronal differentiation,
there is no doubt that sphingosine kinases and S1P receptors are excellent
candidate targets for drug discovery. Moreover, we are also focusing on
S1P phosphatase that functions in an unprecedented manner to regulate
sphingolipid biosynthesis and is thus poised to influence cell fate (J.
Cell Biol. 158: 1039, 2002) and cell locomotion (JBC 2004).
Selected Publications
- Hobson, J.P., Rosenfeldt, H.M., Barak, L.M., Olivera, A., Poulton, S.,
Caron, M.G., Milstien, S., and Spiegel, S. (2001) Role of the
sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility.
Science 291: 1800-1803.
- Spiegel, S., and Milstien, S. (2003) Sphingosine-1-phosphate: an enigmatic
signalling lipid. Nature Rev. Mol. Cell Biol. 4, 397-407.
- Olivera, A., H. M. Rosenfeldt, M. Bektas, F. Wang, I. Ishii, J. Chun, S.
Milstien, and S. Spiegel. 2003. Sphingosine kinase type 1 Induces
G12/13-mediated stress fiber formation yet promotes growth and survival
independent of G protein coupled receptors. J. Biol. Chem. 278:46452-46460.
- Jolly, P. S., Bektas, M., Olivera, A., Gonzalez-Espinosa, C., Proia, R.L.,
Rivera, J., Milstien, S., and Spiegel, S. (2004) Transactivation of
sphingosine-1-phosphate receptors by Fc{epsilon}RI triggering is required
for normal mast cell degranulation and chemotaxis. J. Exp. Med.
199:959-970.
- Le Stunff, H., Mikami, A., Giussani, P., Hobson, J.P., Jolly, P.S.,
Milstien, S., and Spiegel, S. (2004) Role of sphingosine-1-phosphate
phosphatase 1 in EGF-induced chemotaxis. J. Biol. Chem. 279:34290-34297.
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