The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function

Abstract

The sphingosine and diacylglycerol kinases form a superfamily of structurally related lipid signaling kinases. One of the striking features of these kinases is that although they are clearly involved in agonist-mediated signaling, this signaling is accomplished with only a moderate (and sometimes no) increase in the enzymatic activity of the enzymes. Here, we summarize findings that indicate that signaling by these kinases is strongly dependent on their localization to specific intracellular sites rather than on increases in enzyme activity. Both the substrates and products of these enzymes are bioactive lipids. Moreover, many of the metabolic enzymes that act on these lipids are found in specific organelles. Therefore, changes in the membrane localization of these signaling kinases have profound effects not only on the production of signaling lipid phosphates but also on the metabolism of the upstream signaling lipids.-Wattenberg, B. W., S. M. Pitson, and D. M. Raben. The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function.

Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice

“…Future experiments should take intracellular distribution of sphingosine kinase proteins into account. While the activation of SphK1 leads to reduced apoptosis and improved proliferation, activation of SphK2 has been associated with enhanced cell death (Liu et al, 2003), which has been attributed to differential localisation in ER vs cytosol (Wattenberg et al, 2006). Neither SphK1 nor SphK2 has been detected in mitochondria.…”

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

“…As for the activation of catalytic process by the enzyme on MVEs, it may mainly be regulated by its translocation of SphK2 from the cytoplasm to the membrane compartments of MVEs where the substrate sphingosine is enriched 51,52 , although direct enzyme activation, such as by phosphorylation 53 , may contribute to some extent. We have also shown that this continuous S1P signalling is indispensable to the cargo sorting into exosomal ILVs.…”

Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

“…However, the signaling mechanisms responsible for BCR/ABL-induced regulation of Mcl-1 expression in CML cells remain unclear. Recently, sphingosine kinase-1 (SPK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), could be activated by a number of growth factors and intracellular oncoproteins, and has been proven to be involved in signal transduction (Duan et al, 2004;Granata et al, 2004;Wattenberg et al, 2006). SPK1 activation is involved in the multistep progression and multidrug resistance of leukemia (Le Scolan et al, 2005;Bonhoure et al, 2006).…”