Sphingosine kinase (SphK), categorized as a bioactive lipid enzyme, is a central player in the sphingolipid rheostat. The sphingolipid rheostat was first coined in the mid-nineties to describe the repression of ceramide-mediated programmed cell death through the conversion of sphingosine, a metabolite of ceramide, to sphingosine-1-phosphate (S1P). In this role, SphK modulates the balance between S1P, sphingosine and ceramides to maintain physiological levels of sphingosine and ceramide. Activity of SphK/S1P is enhanced through cytokines, hormones, and growth factor stimulation. SphK is the rate-limiting enzyme that maintains the level of S1P for cell survival and normal cell proliferation and function. Conversely, S1P is enzymatically degraded by S1P lyase to maintain the level of S1P at normal physiological levels.  SphK has two major isoenzymes (isozymes), SphK1 and SphK2, and each isozyme is expressed as a number of isoforms. Differences in conformation and dimerization properties, in addition to the varying subcellular localizations of SphK isozymes and isoforms, contribute to the diversity in SphK functions. SphK isozymes have some redundancy and compensatory functions in “normal” physiology, as described in mouse models. SphK knockout mice with deletion of either isozyme show no obvious phenotypic abnormalities. Deletion of both isozymes results in embryonic fatality. Overexpression of SphK1 has been reported as a driver for many types of cancer. 
Estrogen stimulates SphK1 to promote breast cancer development and is also associated with breast cancer treatment resistance. SphK1 mediates insulin-like growth factor binding protein-3 (IGFBP-3) growth factor signaling in breast cells, where overexpression of IGFBP-3 is associated with cancer progression. Proinflammatory cytokines, immunoglobulin receptors, small GTPases, calcium and protein kinase activators, are all described as mediators of SphK1/S1P activity. For example, interleukin 1 (IL-1) stimulates SphK1 (not SphK2) in the brain contributing to chronic neuroinflammation and stimulation of malignant glial cells correlating with poor prognosis for patients with glioblastoma multiforme. SphK1 localized in the cytoplasm has been demonstrated to interact with the tumor necrosis factor-(TNF) receptor associated factor 2 (TRAF2), enhancing S1P activity associated with pro-survival cell signaling of S1P. The SphK2 isozyme contains nuclear import and export sequences, allowing shuttling between the nucleus and cytoplasm [240]. In the nucleus SphK2 complexes with histone H3 and histone deacetylase 1 and 2 (HDAC 1/2) producing S1P that regulates histone acetylation, as part of gene regulation.


1.Hatoum D, et al. Oncotarget. 2017;8(22):36898–36929.