Lay Summary

Our laboratory is studying a natural lipid called sphingosine-1-phosphate (S1P) found in most human cells and in the bloodstream. S1P is important for many biological functions, including blood vessel development, wound healing and immunity. How does one lipid molecule influence so many different processes? S1P activates signals that stimulate cell survival, migration and proliferation and block a form of controlled cell death called apoptosis. Intracellular levels of S1P are tightly regulated by the actions of three enzymes: sphingosine kinase, which is responsible for its synthesis and S1P phosphatase and S1P lyase, which are responsible for its degradation. By regulating the levels of S1P inside the cell, these enzymes help determine whether an injured cell lives or dies. Our laboratory is focused on understanding the role these enzymes play in regulating cell survival during animal development, immunity cancer formation and cancer progression.

Scientific Overview

Functions of S1P in human physiology & pathophysiology

Our laboratory is interested in sphingosine-1-phosphate (S1P) and its role in cell fate decisions, animal development and cancer. What is S1P, and how can one molecule be involved in so many different things? Sphingolipids are ubiquitous membrane constituents whose metabolites function in signal transduction pathways in eukaryotic cells. Sphingosine-1-phosphate (S1P) is a key sphingolipid signaling molecule that regulates cell proliferation, motility and programmed cell death. These effects of S1P and similar phosphorylated sphingoid bases have been observed in organisms as diverse as yeast and humans. In mammalian cells, S1P can act through two distinct mechanisms, as an intracellular second messenger and as a ligand for a family of widely-expressed G protein-coupled receptors. Intracellular levels of S1P are tightly regulated by the actions of sphingosine kinase (SK), which is responsible for its synthesis and S1P phosphatase (S1PP) and S1P lyase (SPL), the two enzymes responsible for its catabolism. SK has recently been shown to function as an oncogene in humans, probably by increasing intracellular S1P levels, stimulating proliferation and inhibiting programmed cell death. Numerous proto-oncogenes have normal roles in development. By regulating cell proliferation, migration, differentiation and apoptosis, these genes contribute to normal embryogenesis. However, if such genes are mutated in a somatic cell, regulation may be lost and proliferative advantage, invasiveness, and failure to respond properly to stress can individually and collectively contribute to malignant transformation and progression. It is, thus, not surprising that we and others are finding S1P to be a central regulator of cell fate decisions and animal development, and the genes that modulate S1P metabolism and signaling to be affected in cancer.