Regulation of the Sphingosine Kinase/Sphingosine 1-Phosphate Pathway

Abstract

Sphingolipids have emerged as pleiotropic signaling molecules with roles in numerous cellular and biological functions. Defining the regulatory mechanisms governing sphingolipid metabolism is crucial in order to develop a complete understanding of the biological functions of sphingolipid metabolites. The sphingosine kinase/ sphingosine 1-phosphate pathway was originally thought to function in the irreversible breakdown of sphingoid bases; however, in the last few decades it has materialized as an extremely important signaling pathway involved in a plethora of cellular events contributing to both normal and pathophysiological events. Recognition of the SK/S1P pathway as a second messaging system has aided in the identification of many mechanisms of its regulation; however, a cohesive, global understanding of the regulatory mechanisms controlling the SK/S1P pathway is lacking. In this chapter, the role of the SK/S1P pathway as a second messenger is discussed, and its role in mediating TNF-α- and EGF-induced biologies is examined. This work provides a comprehensive look into the roles and regulation of the sphingosine kinase/ sphingosine 1-phosphate pathway and highlights the potential of the pathway as a therapeutic target.

Sphingolipids and mitochondrial apoptosis

“…The subcellular location of SK2 is highly debated, but data suggests that it could be localized to the ER, mitochondria, and nuclei (Antoon et al 2011; Don and Rosen 2009; Hait et al 2007; Igarashi et al 2003; Liu et al 2000; Liu et al 2003; Weigert et al 2010). S1P has been shown to be protective/ anti-apoptotic, although data suggests that S1P may also exert a pro-apoptotic role under certain circumstances (Gandy and Obeid 2013; Heffernan-Stroud and Obeid 2013; Pitson 2011; Zhang et al 2014). The subcellular localization in which S1P is generated and the ratio of S1P to ceramide/ sphingosine most likely dictate whether S1P exerts a pro- or anti-apoptotic function.…”

Sphingosine kinase 1 regulates measles virus replication

“…Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid mediator and its level is tightly regulated by cellular enzymes (Gandy and Obeid, 2013; Rosen et al, 2013). Sphingosine kinase (SK) converts sphingosine to S1P via its kinase activity.…”

Sphingolipid regulation of ezrin, radixin, and moesin proteins family: Implications for cell dynamics

“…S1P is a potent bioactive sphingolipid that exerts its function either through intracellular interactions, or by being transported to cell exterior via the ABC transporter family [35] and/or the spinster-2-transporter [36], where it acts on G-protein coupled receptors (S1P receptors; S1PR). Five S1PRs have been identified (S1P1–5).…”