| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 278, Issue 47, 47281-47290, November 21, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
¶
From the
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501 and Department of Transplantation and Immunology, Novartis Institutes for BioMedical Research, Basel, Switzerland
FTY720, a potent immunosuppressive agent, is phosphorylated in vivo into FTY720-P, a high affinity agonist for sphingosine 1-phosphate (S1P) receptors. The effects of FTY720 on vascular cells, a major target of S1P action, have not been addressed. We now report the metabolic activation of FTY720 by sphingosine kinase-2 and potent activation of vascular endothelial cell functions in vitro and in vivo by phosphorylated FTY720 (FTY720-P). Incubation of endothelial cells with FTY720 resulted in phosphorylation by sphingosine kinase activity and formation of FTY720-P. Sphingosine kinase-2 effectively phosphorylated FTY720 in the human embryonic kidney 293T heterologous expression system. FTY720-P treatment of endothelial cells stimulated extracellular signal-activated kinase and Akt phosphorylation and adherens junction assembly and promoted cell survival. The effects of FTY720-P were inhibited by pertussis toxin, suggesting the requirement for Gi-coupled S1P receptors. Indeed, transmonolayer permeability induced by vascular endothelial cell growth factor was potently reversed by FTY720-P. Furthermore, oral FTY720 administration in mice potently blocked VEGF-induced vascular permeability in vivo. These findings suggest that FTY720 or its analogs may find utility in the therapeutic regulation of vascular permeability, an important process in angiogenesis, inflammation, and pathological conditions such as sepsis, hypoxia, and solid tumor growth.
Received for publication, June 27, 2003 , and in revised form, September 2, 2003.
* This work is supported by National Institutes of Health Grants HL67330 and HL70694 (to T. H.) and CA-64436 (to K. C.). The costs publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
These authors contributed equally to this study.
¶ To whom correspondence should be addressed: Center for Vascular Biology, Dept. of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3501. Tel.: 860-679-4128; Fax: 860-679-1201; E-mail: hla{at}nso2.uchc.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Kohno and Y. Igarashi Attenuation of cell motility observed with high doses of sphingosine 1-phosphate or phosphorylated FTY720 involves RGS2 through its interactions with the receptor S1P Genes Cells, July 1, 2008; 13(7): 747 - 757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. N. Gavrilovskaya, E. E. Gorbunova, N. A. Mackow, and E. R. Mackow Hantaviruses Direct Endothelial Cell Permeability by Sensitizing Cells to the Vascular Permeability Factor VEGF, while Angiopoietin 1 and Sphingosine 1-Phosphate Inhibit Hantavirus-Directed Permeability J. Virol., June 15, 2008; 82(12): 5797 - 5806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Metzler, P. Gfeller, G. Wieczorek, J. Li, B. Nuesslein-Hildesheim, A. Katopodis, M. Mueller, and V. Brinkmann Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure Int. Immunol., May 1, 2008; 20(5): 633 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Allende, D. Zhou, D. N. Kalkofen, S. Benhamed, G. Tuymetova, C. Borowski, A. Bendelac, and R. L. Proia S1P1 receptor expression regulates emergence of NKT cells in peripheral tissues FASEB J, January 1, 2008; 22(1): 307 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Sankala, N. C. Hait, S. W. Paugh, D. Shida, S. Lepine, L. W. Elmore, P. Dent, S. Milstien, and S. Spiegel Involvement of Sphingosine Kinase 2 in p53-Independent Induction of p21 by the Chemotherapeutic Drug Doxorubicin Cancer Res., November 1, 2007; 67(21): 10466 - 10474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Westhoff, S. Schmidt, P. Glander, L. Liefeld, S. Martini, G. Offermann, H. H. Neumayer, W. Zidek, M. van der Giet, and K. Budde The impact of FTY720 (fingolimod) on vasodilatory function and arterial elasticity in renal transplant patients Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2354 - 2358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, V. R. Drel, I. G. Obrosova, and P. Pacher Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H610 - H619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sanchez, A. Skoura, M. T. Wu, B. Casserly, E. O. Harrington, and T. Hla Induction of Vascular Permeability by the Sphingosine-1-Phosphate Receptor-2 (S1P2R) and its Downstream Effectors ROCK and PTEN Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1312 - 1318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. C. Hait, A. Bellamy, S. Milstien, T. Kordula, and S. Spiegel Sphingosine Kinase Type 2 Activation by ERK-mediated Phosphorylation J. Biol. Chem., April 20, 2007; 282(16): 12058 - 12065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Oo, S. Thangada, M.-T. Wu, C. H. Liu, T. L. Macdonald, K. R. Lynch, C.-Y. Lin, and T. Hla Immunosuppressive and Anti-angiogenic Sphingosine 1-Phosphate Receptor-1 Agonists Induce Ubiquitinylation and Proteasomal Degradation of the Receptor J. Biol. Chem., March 23, 2007; 282(12): 9082 - 9089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Keul, M. Tolle, S. Lucke, K. von Wnuck Lipinski, G. Heusch, M. Schuchardt, M. van der Giet, and B. Levkau The Sphingosine-1-Phosphate Analogue FTY720 Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 607 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Keller, P. Rivera Gil, M. Tolle, M. van der Giet, J. Chun, H. H. Radeke, M. Schafer-Korting, and B. Kleuser Immunomodulator FTY720 Induces Myofibroblast Differentiation via the Lysophospholipid Receptor S1P3 and Smad3 Signaling Am. J. Pathol., January 1, 2007; 170(1): 281 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kimura, T. Ohmori, R. Ohkawa, S. Madoiwa, J. Mimuro, T. Murakami, E. Kobayashi, Y. Hoshino, Y. Yatomi, and Y. Sakata Essential Roles of Sphingosine 1-Phosphate/S1P1 Receptor Axis in the Migration of Neural Stem Cells Toward a Site of Spinal Cord Injury Stem Cells, January 1, 2007; 25(1): 115 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. Maines, K. J. French, E. B. Wolpert, D. A. Antonetti, and C. D. Smith Pharmacologic Manipulation of Sphingosine Kinase in Retinal Endothelial Cells: Implications for Angiogenic Ocular Diseases Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 5022 - 5031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kohno, M. Momoi, M. L. Oo, J.-H. Paik, Y.-M. Lee, K. Venkataraman, Y. Ai, A. P. Ristimaki, H. Fyrst, H. Sano, et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol. Cell. Biol., October 1, 2006; 26(19): 7211 - 7223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. French, J. J. Upson, S. N. Keller, Y. Zhuang, J. K. Yun, and C. D. Smith Antitumor Activity of Sphingosine Kinase Inhibitors J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 596 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. W. Wattenberg, S. M. Pitson, and D. M. Raben The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function J. Lipid Res., June 1, 2006; 47(6): 1128 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Zemann, B. Kinzel, M. Muller, R. Reuschel, D. Mechtcheriakova, N. Urtz, F. Bornancin, T. Baumruker, and A. Billich Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720 Blood, February 15, 2006; 107(4): 1454 - 1458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Pabst, H. Herbrand, S. Willenzon, T. Worbs, A. Schippers, W. Muller, G. Bernhardt, and R. Forster Enhanced FTY720-Mediated Lymphocyte Homing Requires G{alpha}i Signaling and Depends on beta2 and beta7 Integrin J. Immunol., February 1, 2006; 176(3): 1474 - 1480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. LaMontagne, A. Littlewood-Evans, C. Schnell, T. O'Reilly, L. Wyder, T. Sanchez, B. Probst, J. Butler, A. Wood, G. Liau, et al. Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization Cancer Res., January 1, 2006; 66(1): 221 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mehta and A. B. Malik Signaling Mechanisms Regulating Endothelial Permeability Physiol Rev, January 1, 2006; 86(1): 279 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. I. Singer, M. Tian, L. A. Wickham, J. Lin, S. S. Matheravidathu, M. J. Forrest, S. Mandala, and E. J. Quackenbush Sphingosine-1-Phosphate Agonists Increase Macrophage Homing, Lymphocyte Contacts, and Endothelial Junctional Complex Formation in Murine Lymph Nodes J. Immunol., December 1, 2005; 175(11): 7151 - 7161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K. Lee, K. Man, J. W. Ho, X. H. Wang, R. T.P. Poon, Y. Xu, K. T. Ng, A. C. Chu, C. K. Sun, I. O. Ng, et al. FTY720: A Promising Agent for Treatment of Metastatic Hepatocellular Carcinoma Clin. Cancer Res., December 1, 2005; 11(23): 8458 - 8466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kharel, S. Lee, A. H. Snyder, S. L. Sheasley-O'Neill, M. A. Morris, Y. Setiady, R. Zhu, M. A. Zigler, T. L. Burcin, K. Ley, et al. Sphingosine Kinase 2 Is Required for Modulation of Lymphocyte Traffic by FTY720 J. Biol. Chem., November 4, 2005; 280(44): 36865 - 36872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Howe, S.-H. Chang, K. C. Tolle, R. Dillon, L. J.T. Young, R. D. Cardiff, R. A. Newman, P. Yang, H. T. Thaler, W. J. Muller, et al. HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice Cancer Res., November 1, 2005; 65(21): 10113 - 10119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bandhuvula, Y. Y. Tam, B. Oskouian, and J. D. Saba The Immune Modulator FTY720 Inhibits Sphingosine-1-phosphate Lyase Activity J. Biol. Chem., October 7, 2005; 280(40): 33697 - 33700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Yopp, J. C. Ochando, M. Mao, L. Ledgerwood, Y. Ding, and J. S. Bromberg Sphingosine 1-Phosphate Receptors Regulate Chemokine-Driven Transendothelial Migration of Lymph Node but Not Splenic T Cells J. Immunol., September 1, 2005; 175(5): 2913 - 2924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W.Y. Ho, K. Man, C. K. Sun, T. K. Lee, R. T.P. Poon, and S. T. Fan Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma Mol. Cancer Ther., September 1, 2005; 4(9): 1430 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Halin, M. L. Scimone, R. Bonasio, J.-M. Gauguet, T. R. Mempel, E. Quackenbush, R. L. Proia, S. Mandala, and U. H. von Andrian The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches Blood, August 15, 2005; 106(4): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yin and M. A. Watsky LPA and S1P Increase Corneal Epithelial and Endothelial Cell Transcellular Resistance Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 1927 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Chang, Y. Ai, R. M. Breyer, T. F. Lane, and T. Hla The Prostaglandin E2 Receptor EP2 Is Required for Cyclooxygenase 2-Mediated Mammary Hyperplasia Cancer Res., June 1, 2005; 65(11): 4496 - 4499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mehta, M. Konstantoulaki, G. U. Ahmmed, and A. B. Malik Sphingosine 1-Phosphate-induced Mobilization of Intracellular Ca2+ Mediates Rac Activation and Adherens Junction Assembly in Endothelial Cells J. Biol. Chem., April 29, 2005; 280(17): 17320 - 17328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tolle, B. Levkau, P. Keul, V. Brinkmann, G. Giebing, G. Schonfelder, M. Schafers, K. v. W. Lipinski, J. Jankowski, V. Jankowski, et al. Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P3 Circ. Res., April 29, 2005; 96(8): 913 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Davis, J. J. Clemens, T. L. Macdonald, and K. R. Lynch Sphingosine 1-Phosphate Analogs as Receptor Antagonists J. Biol. Chem., March 18, 2005; 280(11): 9833 - 9841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Chi and R. A. Flavell Cutting Edge: Regulation of T Cell Trafficking and Primary Immune Responses by Sphingosine 1-Phosphate Receptor 1 J. Immunol., March 1, 2005; 174(5): 2485 - 2488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Graler, M.-C. Huang, S. Watson, and E. J. Goetzl Immunological Effects of Transgenic Constitutive Expression of the Type 1 Sphingosine 1-Phosphate Receptor by Mouse Lymphocytes J. Immunol., February 15, 2005; 174(4): 1997 - 2003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Allende, T. Sasaki, H. Kawai, A. Olivera, Y. Mi, G. van Echten-Deckert, R. Hajdu, M. Rosenbach, C. A. Keohane, S. Mandala, et al. Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720 J. Biol. Chem., December 10, 2004; 279(50): 52487 - 52492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Paik, A. Skoura, S.-S. Chae, A. E. Cowan, D. K. Han, R. L. Proia, and T. Hla Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization Genes & Dev., October 1, 2004; 18(19): 2392 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Kunzendorf, E. Ziegler, and D. Kabelitz FTY720--the first compound of a new promising class of immunosuppressive drugs Nephrol. Dial. Transplant., July 1, 2004; 19(7): 1677 - 1681. [Full Text] [PDF]
|
|
|
|
|
|
M. L. Allende, J. L. Dreier, S. Mandala, and R. L. Proia Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration J. Biol. Chem., April 9, 2004; 279(15): 15396 - 15401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Saba and T. Hla Point-Counterpoint of Sphingosine 1-Phosphate Metabolism Circ. Res., April 2, 2004; 94(6): 724 - 734. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
