SK1

SK1, or sphingosine kinase 1, is a lipid kinase that phosphorylates sphingosine to produce sphingosine-1-phosphate (S1P), a potent signaling molecule. In humans it is encoded by the SPHK1 gene. Along with sphingosine kinase 2 (SK2, encoded by SPHK2), SK1 participates in sphingolipid signaling that influences cell proliferation, survival, migration, and angiogenesis.

Biochemical properties: SK1 is activated by mitogenic signals and can be phosphorylated by ERK at a conserved serine residue, promoting translocation from the cytosol to the plasma membrane and increasing catalytic activity. Regulation also involves ubiquitination and proteasomal degradation, providing a mechanism for turning off signaling.

Mechanism of action: S1P produced by SK1 can act inside the cell or be exported to act on five G protein-coupled S1P receptors (S1PR1–S1PR5), initiating signaling cascades that influence vascular development, immune cell trafficking, and tumor progression. The pathway is often described as "inside-out" signaling.

Biological roles and disease relevance: SK1 plays roles in development and immune responses; dysregulation is linked to cancer, inflammation, and metabolic disorders. In many cancers, elevated SK1 activity or expression correlates with tumor growth, survival, and resistance to therapy, making SK1 a target of interest for drug development.

Therapeutic perspective: Selective SK1 inhibitors such as PF-543 have been used to study the enzyme's role in vitro; other inhibitors, including less selective compounds, are used in research. No SK1-targeted therapeutics have been approved for clinical use as of now.