Role of Sphingosine Kinase 2 in Cell Migration toward Epidermal Growth Factor

Sphingosine Kinase 2 is a highly conserved enzyme found in organisms as diverse as mammals, flies, worms, slime mold, yeast, and plants that catalyzes the phosphorylation of sphingosine to generate sphingosine 1-phosphate (S1P), a potent lipid mediator . As a specific ligand for a family of five G protein-coupled receptors, S1P1–5 , S1P regulates a wide variety of important cellular processes, including cytoskeletal rearrangements and cell movement, angiogenesis and vascular maturationand immunity and lymphocyte trafficking . In many cell types, binding of S1P to S1P1 or S1P3 induces chemotaxis , whereas binding to S1P2 inhibits it .
Sphingosine Kinase 2 has recently been shown to control T lymphocyte egress from thymus and peripheral lymphoid organs, and it has been suggested that cyclical ligand-induced modulation of S1P1 contributes to lymphoid organ transit time of lymphocytes . Moreover, ligation of S1P1 leads to transactivation of VEGFR2/Flk-1 and produces PDGF, growth factors that initiate signaling cascades important for movement and vascular remodeling. In addition, a reciprocal mechanism of transactivation is important in cell movement toward growth factors, like PDGF, or toward antigen.
According to this paradigm, activation of PDGFR or cross-linking of the high affinity IgE receptor FcϵRI stimulates and translocates Sphingosine Kinase 2 to the plasma membrane, resulting in spatially restricted formation of S1P. S1P, in turn, activates S1P1, a critical event for directed cell movement toward PDGF or antigen. Conversely, binding of S1P to S1P2 decreases chemotaxis.