Kinases sphingosine

SIP is formed from sphingosine by sphingosine kinases (SphKs). Degradation of SIP occurs either reversibly by lipid phosphate phosphohydrolases (LPPs) and SIP phosphatases (SPPs), or irreversibly by SIP lyase (SPL) (Fig. 1). The localization of SIP production is highly important since SIP plays a role both as extracellular mediator and as intracellular... 

Sphingosine kinases (SphKs) catalyse the phosphorylation of sphingosine to sphingosine-1 -phosphate (SIP). 

Auge, N., Nikolova-Karakashian, M., Carpentier, S., Parthasarathy, S., Negre-Salvayre, A., Salvayre, R., Merrill, A.H. Jr, Levade, T, 1999, Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized LDL in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase, J. Biol. Chem. 274 21533-21538. 

In another line of inveshgation, Auge et al. (1999) showed that heatment of vascular smooth muscle cells with oxidized LDL shmulated sphingomyelinases, CDases, and sphingosine kinase achvihes, leading to the production of SIP which as these authors suggested, promotes the proliferation of these cells. 

Sphingosine kinase expression incieases intracellular sphingosine-l-phosphate and promotes ceU growth and survival. J. Cell. Biol. 147 545-558. 

The intracellular concentrations of sphingosine and SIP are governed by the activities of enzymes that catalyse their synthesis and removal. These include ceramidase, sphingosine kinase (SPHK), SIP phosphatase and SIP lyase (Figure 1). Several of these enzymes have only recently been cloned and knowledge of their respective roles and regulation is incomplete. 

Buehter, B.M., Bardes, E.S and Bell, R.M., 1996, Protein kinase C-dependent regulation of human erthyroleukemia (HEL) ceU sphingosine kinase activity, Biochim. Biophys. Acta 1303 233-242. 

Choi, O.H., Kim, J.H. and Kinet, J.P., 1996, Calcium mobihsation via sphingosine kinase in signaling by the FceRI antigen receptor. Nature (London) 380 634-636. 

De Jonge, S., Van Overmeire, 1., Poulton, S., Hendrix, J., Busson, R., Van Calenbergh, S., De Keukeleire, D., Spiegel, S. Herdewijn, P., 1999, Structure-activity relationship of short-chain sphingoid bases as inhibitors of sphingosine kinase, Bioorg. Med. Chem. Lett. 9 3175-3180. 

EdsaU, L.C., CuvUlier, O., Twitty, S., Spiegel, S. and MUstien, S., 2001, Sphingosine kinase expression regulates apoptosis and caspase activation in PCI 2 ceUs, J. Neurochem. 76 1573-1584. 

Kohama, T., Olivera, A., Edsall, L., Nagiec, M.M., Dickson, R. and Spiegel, S., 1998, Molecular cloning and functional characterization of murine sphingosine kinase, J. Biot. Chem. 273 23722-23728. 

Melendez, A., Floto, R.A., Gillooly, D.J., Harriett, M.M and Allen, J.M., 1998, FcyRI coupling to phospholipase D initiates sphingosine kinase-mediated calcium mobilization and vesicular trafficking, J. Biol. Chem. 273 9393-9402. 

Meyer zu Heiingdoif, D.M., Lass, H., Alemany, R., Laser, K.T., Neumann, R, Zhang, C., Schmidt, M., Rauen, Lf., Jakobs, K.H. and Van Koppen, C.J., 1998, Sphingosine kinase-mediated signaling by G-protein-coupled receptors, EMBO J. 17 2830-2837. 

Ohvera, A., Edsall, L., Poulton, S., Kazlauskas, A. and Spiegel, S., 1999, Platelet-derived growth factor-induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLCy, FASEB J. 13 1593-1600. 

Xia, P., Wang, L, Gamble, J.R. and Vadas, M.A., 1999, Activation of sphingosine kinase by tumor necrosis factor-a inhibits apoptosis in human endothelial ceUs, J. Biol. Chem. 274 34499-34505. 

Yatomi, Y., Ruan, F Megidish, T., Toyokumi, T., Hakomori, S. and Igarashi, Y., 1996, N,N-dimethylsphingosine inhibition of sphingosine kinase and sphingosine 1-phosphate activity in human platelets, Biochem. J. 35 626-633. 

Kleuser, B., Cuvillier, O., and Spiegel, S., 1998, la,25-dihydroxy vitamin D3 inhibits programmed cell death in HL-60 cells by activation of sphingosine kinase. Cancer Res. 

Apart from PKA, some other protein-kinases were found to be controlled by forskolin, such as cytosolic sphingosine kinase in rat periosteal cells [186] and protein kinase B (PKB) [187]. The latter was found to be stimulated by the activation of PKA through a PI3 (phosphatidylinositol 3)-kinase-independent pathway. Furthermore, a distinct activation mechanism was suspected, other than that normally observed by growth factors such as insulin, since substitution of the serine at the S473 position of PKB with alanine could not prevent activation by forskolin. The JAK family of protein kinases in T lymphocytes can also be regulated by forskolin through the activation of PKA [188]. Thus it seems obvious that many other enzymes could be susceptible to control by forskolin. 

Stoffel, W., Heimann, G., and Hellenbroich, B., Sphingosine kinase in blood platelets, Hoppe-Seylers Z. Physiol. Chem., 354, 562, 1973. 

Sphingosine kinase 1 (sphkl) Sphingosine kinase 2 (sphk2)... 

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