Mammalian sphingosine kinase type 2 isoforms, cloning,...

Details Mammalian sphingosine kinase type 2 isoforms, cloning,... Mammalian sphingosine kinase type 2 isoforms, cloning,...

2001-03-26

2004-10-05

Achutamurthy, Ponnathapu (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Transferase other than ribonuclease

C536S023200

Reexamination Certificate

active

06800470

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns mammalian (such as mouse and human) sphingosine kinase type 2 isoforms, the molecular cloning of such isoforms and methods of use of such isoforms. Sphingosine kinase type 2 has distinct characteristics when compared to sphingosine kinase type 1.
2. Background Information
Sphingosine-1-phosphate (SPP) is a bioactive sphingolipid metabolite which regulates diverse biological processes acting both inside cells as a second messenger to regulate proliferation and survival and outside cells as a ligand for G-protein coupled receptors of the EDG-1 subfamily (Spiegel, S.,
J. Leukoc. Biol.,
65, (1999), 341-344; Goetzl, E. J., An, S.
FASEB J.,
12, (1998), 1589-1598). Thus, SPP plays important roles as a second messenger to regulate cell growth and survival (Olivera, A., Spiegel, S., Nature, 365, (1993), 557-560; Cuvillier, O., Pirianov, G., Kleuser, B., Vanek, P. G., Coso, O. A., Gutkind, S., and Spiegel, S.,
Nature,
381, (1996), 800-803).
Many external stimuli, particularly growth and survival factors, activate sphingosine kinase (“SPHK”), the enzyme that forms SPP from sphingosine. This rapidly growing list includes platelet-derived growth factor (“PDGF”) (Olivera, A., Spiegel, S.,
Nature,
365, (1993), 557-560; Pyne, S., Chapman, J. Steele, L., and Pyne, N. J.,
Eur. J. Biochem.,
237, (1996), 819-826; Coroneos, E., Martinez, M., McKenna, S. and Kester, M.,
J. Biol. Chem.,
270, (1995), 23305-23309), nerve growth factor (“NGF”) (Edsall, L. C., Pirianov, G. G., and Spiegel, S.,
J. Neurosci.,
17, (1997), 6952-6960; Rius, R. A., Edsall, L. C., and Spiegel, S.,
FEBS Lett.,
417, (1997), 173-176), vitamin D3 (Kleuser, B., Cuvillier, O., and Spiegel, S.,
Cancer Res.,
58, (1998) 1817-1824), muscarinic acetylcholine agonists (Meyer zu Heringdorf, D., Lass, H., Alemany, R., Laser, K. T., Neumann, E. Zhang, C., Schmidt, M., Rauen, U., Jakobs, K. H., and van Koppen, C. J.,
EMBO J.,
17, (1998), 2830-2837), TNF-a (Xia, P., Gamble, J. R., Rye, K. A., Wang, L., Hii, C.S.T., Cockerill, P., Khew-Goodall, Y., Bert, A. G., Barter, P. J., and Vadas, M. A.,
Proc. Natl. Acad. Sci. USA,
95, (1998), 14196-14201), and the cross-linking of the immunoglobulin receptors FceR1 (Choi, O. H., Kim, J. -H., and Kinet, J. -P.,
Nature,
380, (1996), 634-636) and FcgR1 (Melendez, A., Floto, R. A., Gillooly, D. J., Harnett, M. M., and Allen, J. M.,
J. Biol. Chem.,
273 (1998), 9393-9402).
Intracellular SPP, in turn, mobilizes calcium from internal stores independently of InsP3 (Meyer zu Heringdorf, D., Lass, H., Alemany, R., Laser, K. T., Neumann, E. Zhang, C., Schmidt, M., Rauen, U., Jakobs, K. H., and van Koppen, C. J.,
EMBO J.,
17, (1998), 2830-2837; Mattie, M., Brooker, G, and Spiegel, S.,
Biol. Chem.,
269, (1994), 3181-3188), as well as eliciting diverse signaling pathways leading to proliferation (Rani, C. S., Berger, A., Wu, J., Sturgill, T. W., Beitner-Johnson, D., LeRoith, D., Varticovski, L., and Spiegel, S.,
J. Biol. Chem.,
272, (1997), 10777-10783; Van Brocklyn, J. R., Lee, M. J., Menzeleev, R, Olivera, A., Edsall, L., Cuvillier, O., Thomas, D. M., Coopman, P. J. P., Thangada, S., Hla, T., and Spiegel, S.,
J. Cell Biol.,
142, (1998), 229-240) and suppression of apoptosis (Cuvillier, O., Pirianov, G., Kleuser, B., Vanek, P. G., Coso, O. A., Gutkind, S., and Spiegel, S.,
Nature,
381, (1996), 800-803; Edsall, L. C., Pirianov, G. G., and Spiegel, S, J. Neurosci., 17, (1997), 6952-6960; Van Brocklyn, J. R., Lee, M. J., Menzeleev, R., Olivera, A., Edsall, L., Cuvillier, O., Thomas, D. M., Coopman, P. J. P., Thangada, S., Hla, T., and Spiegel S.,
J. Cell Biol.,
142, (1998), 229-240).
Moreover, competitive inhibitors of sphingosine kinase block formation of SPP and selectively inhibit calcium mobilization, cellular proliferation and survival induced by these various stimuli (Spiegel, S.,
J. Leukoc. Biol.,
65, (1999), 341-344). Thus, it has been suggested that the dynamic balance between levels of the sphingolipid metabolites, ceramide and SPP, and the consequent regulation of opposing signaling pathways, is an important factor that determines the fate of cells (Cuvillier, O., Rosenthal, D. S., Smulson, M. E., and Spiegel, S.,
J. Biol. Chem.,
273, (1998), 2910-2916). For example, stress stimuli increase ceramide levels leading to apoptosis, whereas survival factors stimulate SPHK leading to increased SPP levels, which suppress apoptosis (Cuvillier, O., Rosenthal, D. S., Smulson, M. E., and Spiegel, S.,
J. Biol. Chem.,
273, (1998), 2910-2916).
Furthermore, the SPHK pathway, through the generation of SPP, is critically involved in mediating TNF-a-induced endothelial cell activation (Xia, P., Gamble, J. R., Rye, K. A., Wang, L., Hii, C. S. T., Cockerill, P., Khew-Goodall, Y., Bert, A. G., Barter, P. J., and Vadas, M. A.,
Proc. Natl. Acad. Sci. USA,
95, (1998), 14196-14201) and the ability of high density lipoproteins (HDL) to inhibit cytokine-induced adhesion molecule expression has been correlated with its ability to reset this sphingolipid rheostat (Xia, P., Gamble, J. R., Rye, K. A., Wang, L., Hii, C. S. T., Cockerill, P., Khew-Goodall, Y., Bert, A. G., Barter, P. J., and Vadas, M. A.,
Proc. Natl. Acad. Sci. USA,
95, (1998), 14196-14201). This has important implications for the protective function of HDL against the development of atherosclerosis and associated coronary heart disease. Recent data has also connected the sphingolipid rheostat to allergic responses (Prieschl, E., E., Csonga, R., Novotny, V., Kikuchi, G. E., and Baumruker, T.,
J. Exp. Med.,
190, (1999), 1-8).
Interest in SPP has accelerated recently with the discovery that it is a ligand of the G-protein coupled cell surface receptor EDG-1 (Van Brocklyn, J. R., Lee, M. J., Menzeleev, R., Olivera, A., Edsall, L., Cuvillier, O., Thomas, D. M., Coopman, P. J. P., Thangada, S, Hla, T., and Spiegel, S.,
J Cell Biol.,
142, (1998), 229-240; Lee, M. J., Van Brocklyn, J. R., Thangada, S., Liu, C. H., Hand, A. R., Menzeleev, R., Spiegel, S., and Hla, T., Science 279, (1998), 1552-1555). This rapidly led to the identification of several other related receptors, named EDG-3,-5,-6, and -8, which are also specific SPP receptors (Goetzl, E. J., and An, S.,
FASEB J.,
12, (1998), 1589-1598; Spiegel, S., and Milstein, S.,
Biochem.Biophys. Acta.,
1484 (2-3):107-16, (2000)). Sphinganine-1-phosphate, which is structurally similar to SPP and lacks only the trans double bond at the 4-position, but not lysophosphatidic acid or sphingosylphosphorylcholine, also binds to these receptors (Van Brocklyn, J. R., Tu, Z., Edsall, L. C., Schmidt, R. R., and Spiegel, S., J.
Biol. Chem.,
274, (1999) 4626-4632), demonstrating that EDG-1 belongs to a family of G-protein coupled receptors that bind SPP with high affinity and specificity (Goetzl, E. J. and An, S.,
FASEB J.,
12, (1998), 1589-1598; Spiegel, S. and Milstien, S.,
Biochem. Biophys. Acta.,
1484(2-3):107-116, (2000)).
The EDG-1 family of receptors are differentially expressed, mainly in the cardiovascular and nervous systems, and are coupled to a variety of G-proteins and thus can regulate diverse signal transduction pathways culminating in pleiotropic responses depending on the cell type and relative expression of EDG receptors. Although the biological functions of the EDG-1 family of GPCRs are not completely understood, recent studies suggest that binding of SPP to EDG-1 stimulates migration and chemotaxis (Wang, F., Van Brocklyn, J. R., Hobson, J. P., Movafagh, S., Zukowska-Grojec, Z., Milstien, S., and Spiegel, S.
J. Biol. Chem.,
274, (1999), 35343-35350; English, D., Kovala, A. T., Welch, Z., Harvey, K. A., Siddiqui, R. A., Brindley, D. N., and Garcia, J. G.,
J. Hematother. Stem Cell Res.,
8, (1999), 627-634), and as a consequence, may regulate angiogenesis (Wang, F., Van Brocklyn, J. R., Hobson, J. P., Movafagh, S., Zukowska-Grojec, Z., Milstien, S., and Spiegel, S.
J. Biol. Chem.,
274, (1999), 35343-35350; Lee, O. H., Kim, Y. M., Lee, Y. M., Moon, E. J., Lee, D. J., Kim, J. H., Ki

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