Role of sphingosine kinase localization in sphingolipid signaling

Abstract

The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to the plasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.

Sphingosine Kinases: Emerging Structure–Function Insights

“…Subcellular localisation of SK1 and SK2 critically underpins their biochemical roles (reviewed elsewhere [39][40][41][42][43]) and dictates transformation of normal cells into cancer cells [44]. In unstimulated cells, SK1 is a predominantly cytosolic enzyme, but stimulation with a range of agonists can elicit both upregulation of SK1 catalytic activity [45][46][47][48][49][50][51][52][53][54][55] and translocation to the plasma membrane [26,44,[56][57][58][59].…”

Sphingolipids and mitochondrial apoptosis

“…Phosphorylation of sphingosine is catalyzed by sphingosine kinase (SK) (Heffernan-Stroud and Obeid 2013; Lima and Spiegel 2013; Pitson 2011; Pyne et al 2012; Siow et al 2011; Snider 2013; Wattenberg 2010). There are two sphingosine kinases, namely SK1 and SK2.…”

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

“…There are two isoforms of sphingosine kinases (Sphk), Sphk1 and Sphk2, which are ubiquitously expressed in all tissues but differ in expression levels and subcellular localization. [20][21][22] Currently, Sphk1 is regarded as an enzyme involved in prosurvival and proproliferative cascades while the functions and regulations of Sphk2 are not as well characterized and seem to be context dependent. Known Sphk2 functions involve induction of growth arrest and apoptosis, 23,24 but also promotion of survival and proliferation.…”