SPHK1

Sphingosine kinase 1 (SphK1) is a cytosolic enzyme that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P), a potent bioactive lipid mediator. In humans, the enzyme is encoded by the SPHK1 gene and is broadly expressed across tissues. SphK1 functions within the sphingolipid metabolic pathway, balancing levels of pro-survival S1P with pro-apoptotic ceramide and sphingosine.

The catalytic reaction requires ATP and a divalent cation (typically Mg2+) and yields S1P, which can be dephosphorylated back to sphingosine or cleaved by S1P lyase. S1P is also exported from cells and signals in an autocrine or paracrine manner by binding to a family of G protein-coupled receptors, S1PR1–S1PR5, influencing numerous biological processes beyond the cell of origin.

Localization and activity of SphK1 are dynamically regulated. It is primarily cytosolic but can translocate to the plasma membrane upon activation, increasing local S1P production. Regulation occurs through phosphorylation (notably by MAP kinases such as ERK1/2) and interactions with regulatory proteins; additional signaling inputs from growth factors and cytokines modulate its activity.

Physiologically, SphK1 participates in cell growth, survival, migration, and angiogenesis, and it influences immune cell trafficking via S1P signaling gradients. Pathologically, dysregulation of SphK1 has been linked to cancer, inflammatory and autoimmune diseases, and fibrosis. Pharmacological inhibitors of SphK1, such as PF-543, are studied for research and potential therapeutic use, reflecting its role in disease pathogenesis.