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Published online before print June 13, 2008

0031-6997/08/6002-181-195$7.00
Pharmacol Rev 60:181-195, 2008

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"Inside-Out" Signaling of Sphingosine-1-Phosphate: Therapeutic Targets

Kazuaki Takabe, Steven W. Paugh, Sheldon Milstien and Sarah Spiegel

Division of Surgical Oncology, Department of Surgery (K.T.), Department of Biochemistry and Molecular Biology (S.W.P., S.S.), Virginia Commonwealth University School of Medicine, Richmond, Virginia; and National Institute of Mental Health, Bethesda, Maryland (S.M.)

Abstract
I. Introduction
II. Biosynthesis and Metabolism of Sphingosine 1-Phosphate
III. Mechanisms of Sphingosine Kinase Activation
IV. Sphingosine 1-Phosphate Receptors
V. Sphingosine 1-Phosphate in the Blood
VI. Sphingosine 1-Phosphate in Human Diseases and Sphingosine 1-Phosphate-Targeted Therapies
VII. FTY720 (Fingolimod)
    A. Mechanism of Action
    B. Clinical Trials
VIII. KRP-203
IX. Other Sphingosine 1-Phosphate Receptor Agonists
X. Sphingosine Kinase Inhibitors
XI. Anti-Sphingosine 1-Phosphate Monoclonal Antibody
XII. Conclusions
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody.

Address correspondence to: Dr. Sarah Spiegel, Professor and Chair, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, 1101 E. Marshall St., 2011 Sanger Hall, Richmond, VA 23298. E-mail: sspiegel{at}vcu.edu






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