Molecular mechanisms of regulation of sphingosine kinase 1

Abstract

Within the last 3 decades, there has been intense study of bioactive sphingolipids and the enzymes which metabolize those lipids. One enzyme is the critical lipid kinase sphingosine kinase 1 (SK1), which produces the potent and pleiotropic signaling lipid, sphingosine 1-phosphate (S1P). SK1 and S1P have been implicated in a host of different diseases including cancer, chronic inflammation, and metabolic diseases. However, while there is ample knowledge about the importance of these molecules in the development and progression of disease there is a dearth of knowledge of the molecular mechanisms which regulate SK1 function. In this review, we will cover some of the more recent and exciting findings about the different ways SK1 function can be regulated, from transcriptional regulation to protein stability. Finally, we will delve into recent structural insights into SK1 and how they might relate to function at cell membranes.

Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1

“…Another study localized L194, F197, and L198 within a hydrophobic patch on the surface of SphK1 and demonstrated that hSphK1-L194Q and hSphK1-F197A-L198Q did not bind to acidic liposomes in vitro and were not recruited to tubular membrane invaginations induced by cholesterol extraction in living cells [ 4 ]. Hence, this hydrophobic patch is regarded as essential for curvature-sensitive membrane binding of SphK1 [ 9 , 21 ]. We show here that the two hSphK1 mutants, hSphK1-L194Q-GFP and hSphK1-F197A-L198Q-GFP, did not visibly translocate to the plasma membrane in response to M 3 receptor activation in HEK-293 cells ( Figure 5 A–C).…”

“…There are two SphK isoforms, which are derived from different genes and differ in tissue expression, structure, subcellular localization, regulation, and function. SphK2 has been observed in the cytosol, ER, mitochondria, and nucleus, whereas SphK1 is mainly found in the cytosol and may translocate to the plasma membrane upon stimulation [ 7 , 8 , 9 , 10 ]. Thus, SphK1 seems to be poised to generate S1P for cellular export, and thereby trigger S1P-GPCR cross-activation, which is known as inside-out signaling.…”

“…SphK1 is regulated transcriptionally, translationally, and post-translationally by many different pathways [ 8 , 9 , 10 ]. Acute activation of SphK1, with or without membrane translocation, can be induced by growth factors (for example PDGF, epidermal growth factor, nerve growth factor), cytokines (for example tumor necrosis factor-α, interleukin-1β, transforming growth factor-β), immunoglobulin receptors, or GPCRs (for review, see [ 8 , 9 , 10 ]). Several mechanisms have been described for plasma membrane translocation of SphK1.…”

Targeting sphingosine kinase 1 (SK1) enhances oncogene-induced senescence through ceramide synthase 2 (CerS2)-mediated generation of very-long-chain ceramides

“…This extends our previous study connecting oncogenic K-Ras to SK1, and the current results suggest K-Ras regulates SK1 translation or protein stability. Of note, several micro RNA (miRNA) and long non-coding RNA (lncRNA) can negatively regulate SK1 translation 68 . Thus, oncogenic suppression of such miRNA and lncRNA could lead to increased SK1 levels.…”

Sphingosine 1-Phosphate in Malaria Pathogenesis and Its Implication in Therapeutic Opportunities

“…Regulation or inhibition of metabolic enzymes, particularly SPHK1 in RBC and deprivation of RBC content of S1P could be a potent therapeutic against malaria infection. A recent article by Pulkoski-Gross and Obeid ( 2018 ) describes SPHK1 regulation at different levels starting from transcription to post-translational modification through the use of long non-coding RNAs, micro RNAs, small interfering RNAs, and physiological and pharmacological stimuli. However, RBC being devoid of nucleus and genetic material, these methods of regulation seem ineffective.…”