Department Directory

Sheldon Milstien, Ph.D.

Sheldon MilstienChief, Unit of Molecular Enzymology
Laboratory of Cellular and Molecular Regulation
Bethesda, MD 20892

Adjunct Professor
Department of Biochemistry & Molecular Biology
Medical College of Virginia Campus
Virginia Commonwealth University
Richmond, VA 23298-0614

Telephone: 804-828-9330


Ph.D., University of Southern California, Los Angeles, CA, 1968, Biochemistry

  • 1968-1972 - Senior Staff Fellow, Laboratory of Chemistry, NIAMD, NIH
  • 1972-1973 - Senior Staff Fellow, Laboratory of Neurochemistry,
  • National Institute of Mental Health, Bethesda, MD
  • 1973-1995 - Research Chemist, Senior Investigator, Laboratory of Neurochemistry,
  • National Institute of Mental Health, Bethesda, MD

Research Role of Sphingolipid Metabolites in Neurobiology

Evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P) in yeast, plants, and mammals have shown it to have important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein coupled receptors. These S1P receptors are differentially expressed, coupled to a variety of G-proteins and regulate angiogenesis, vascular maturation, cardiac development, and immunity, and have important roles in directed cell movement. S1P also has direct intracellular actions. Only very recently have we begun to make progress in understanding the interplay between the intracellular and extracellular functions of S1P. Our recent studies are aimed at understanding these complex roles of S1P in cancer, immune responses, and neurobiology.

Nerve growth factor (NGF), the archetypal neurotrophin, has long been recognized for its role in survival, differentiation, axonal growth, and target innervation of sympathetic and sensory neurons. However, the local signals that regulate neurite extension are not well understood. A new addition to the NGF signaling repertoire is the activation of sphingosine kinase, the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate. We are currently studying the role of sphingosine-1-phosphate in neuronal development and in NGF-induced survival and elaboration of neurites. Our results raise the intriguing possibility that abnormal sphingolipid metabolism could be involved in the progression of neurodegenerative disorders, such as trauma, Alzheimer's, Parkinson's, and ischemic stroke, and that known agents that interfere with or stimulate sphingolipid metabolism might be useful therapeutic agents.

figure 1

Highlights of current findings

There are two isoforms of sphingosine kinase (SphK) that catalyze the formation of S1P. Whereas SphK1 stimulates growth and survival, we surprisingly found that SphK2 enhanced apoptosis in diverse cell types and also suppressed cellular proliferation. SphK2-induced apoptosis was independent of activation of S1P receptors. Sequence analysis revealed that SphK2 contains a 9 amino acid motif similar to that present in BH3-only proteins, a pro-apoptotic subgroup of the Bcl-2 family. We are now examining the intriguing possibility that SphK2 is a bona fide BH3-only protein and determining its mechanism of action.


View Dr. Milstien's Publications via the National Library of Medicine's PubMed.


VCU Department of Biochemistry and Molecular Biology Virginia Commonwealth University VCU Medical Center
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