SPHK1

Sphingosine kinase 1 phosphorylates the sphingolipid sphingosine to generate sphingosine-1-phosphate (S1P), the ligand for a family of five GPCRs, and thereby sets the balance of the so-called sphingolipid rheostat between pro-apoptotic ceramide/sphingosine and pro-survival S1P. SPHK1 is predominantly cytoplasmic and translocates to the plasma membrane after phosphorylation by PKC, where its product can be exported by S1P transporters. Widely expressed and often upregulated in tumors, SPHK1 promotes proliferation, survival, angiogenesis and inflammatory signaling, and it is pursued as a therapeutic target in cancer, fibrosis and immune-mediated disease. SPHK1 activity is itself controlled by phosphorylation, calcium and protein-protein interactions with partners including TRAF2, which couples the kinase to NF-κB activation.