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Review
. 2011 Oct;46(5):365-75.
doi: 10.3109/10409238.2011.580097. Epub 2011 Aug 25.

The Compartmentalization and Translocation of the Sphingosine Kinases: Mechanisms and Functions in Cell Signaling and Sphingolipid Metabolism

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Free PMC article
Review

The Compartmentalization and Translocation of the Sphingosine Kinases: Mechanisms and Functions in Cell Signaling and Sphingolipid Metabolism

Deanna Siow et al. Crit Rev Biochem Mol Biol. .
Free PMC article

Abstract

Members of the sphingosine kinase (SK) family of lipid signaling enzymes, comprising SK1 and SK2 in humans, are receiving considerable attention for their roles in a number of physiological and pathophysiological processes. The SKs are considered signaling enzymes based on their production of the potent lipid second messenger sphingosine-1-phosphate, which is the ligand for a family of five G-protein-linked receptors. Both SK1 and SK2 are intracellular enzymes and do not possess obvious membrane anchor domains within their primary sequences. The native substrates (sphingosine and dihydrosphingosine) are lipids, as are the corresponding products, and therefore would have a propensity to be membrane associated, suggesting that specific membrane localization of the SKs could affect both access to substrate and localized production of product. Here, we consider the emerging picture of the SKs as enzymes localized to specific intracellular sites, sometimes by agonist-dependent translocation, the mechanism targeting these enzymes to those sites, and the functional consequence of that localization. Not only is the signaling output of the SKs affected by subcellular localization, but the role of these enzymes as metabolic regulators of sphingolipid metabolism may be impacted as well.

Figures

Figure 1
Figure 1
(Modified from Siow et al, 2011. Adv. Enzyme Reg. and Wattenberg 2011. World J. Biochem). A. Sphingolipid metabolism. Note that the de novo biosynthesis of sphingolipids begins with the condensation of serine and palmitoyl CoA and that the sole enzyme that can accomplish the degradation of the sphingosine backbone is S1P lyase. Note also that sphingosine kinase can utilize dihydrosphingosine generated during de novo sphingolipid synthesis or sphingosine released from ceramide by ceramidases. B. Structures of sphingolipid intermediates. Note that the double 4,5 double bond in sphingosine is only introduced in the context of dihydroceramide. Therefore all dihydrosphingosine-1-phosphate must be derived from dihydrosphingosine diverted from ceramide biosynthesis.
Figure 1
Figure 1
(Modified from Siow et al, 2011. Adv. Enzyme Reg. and Wattenberg 2011. World J. Biochem). A. Sphingolipid metabolism. Note that the de novo biosynthesis of sphingolipids begins with the condensation of serine and palmitoyl CoA and that the sole enzyme that can accomplish the degradation of the sphingosine backbone is S1P lyase. Note also that sphingosine kinase can utilize dihydrosphingosine generated during de novo sphingolipid synthesis or sphingosine released from ceramide by ceramidases. B. Structures of sphingolipid intermediates. Note that the double 4,5 double bond in sphingosine is only introduced in the context of dihydroceramide. Therefore all dihydrosphingosine-1-phosphate must be derived from dihydrosphingosine diverted from ceramide biosynthesis.
Figure 2
Figure 2
A model of the role of sphingosine kinase localization on substrate utilization and delivery of S1P to specific sites for secretion or loading of intracellular effectors. During agonist stimulation SK1 is phosphorylated by ERK1/2, or a related kinase, resulting in translocation to the plasma membrane (PM). This translocation is mediated by the CIB1 protein and binding to acidic phospholipids. Translocation to the PM enhances secretion of S1P, and ultimately S1P binds to a member of the S1P receptor (S1PR) family. Additionally, SK1 binds in part to TRAF2 and this may load S1P onto TRAF2 to activate the ubiquitin ligase activity of TRAF2. Similarly, the nuclear localization of SK2 is essential for its binding to histones, which may optimize the loading of S1P onto histone deacetylases-1 or -2 (HDAC1/2) and the subsequent inhibition of histone deacetylase activity. Membrane binding of SK1 may specify whether the lipid substrate is sphingosine (Sph) (plasma membrane) or dihydrosphingosine (DH-Sph)(endoplasmic reticulum, ER). Localization of SK1 at the ER diverts dihydrosphingosine from the ceramide biosynthetic pathway. (Note: A color version of this figure is available online).

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