Gabor J. Tigyi


Gabor Tigyi

Chairman and Professor of Physiology, UTHSC
Professor of Physiology and Chemistry, University of Memphis
Harriet S. Van Vleet Chair in Oncology Research
Associate Director for Basic Science UT Cancer Institute
Professor, (adjunct) School of Graduate Sciences, Hokkaido University, Japan

Phone: 901-448-4793
Fax: 901-448-7126
Email: gtigyi@physio1.uthsc.edu
Full CV

Education

M.D. 1982 Medical University of Pecs, Hungary
Ph.D. 1992 Hungary Academy of Sciences, Budapest

Research Interest

LPASphingo

Dr. Tigyi's research is aimed at elucidating the structure and function as well as the signal transduction mechanism of a family of endogenous phospholipids with growth factor-like properties. Dr. Tigyi has shown that serum contains a set of lipid factors that are the major source of mitogenic stimuli present in serum. The best characterized member of this group of lipid mediators is lysophosphatidic acid (LPA). Dr. Tigyi's group has identified the PSP24 receptor gene for LPA and has determined the ligand binding pocket for the EDG family of sphingosine-1-phosphate receptors and LPA receptors. Dr. Tigyi's group has made pioneering contributions to the current understanding of the pharmacology of phospholipid growth factors.

Honors

  • Member, Academie Europeene Des Sciences, Des Art at Des Lettres, Paris, France, 2007
  • Keynote Speaker, University of Tokyo 21st Century COE symposium “Drug discovery and Chemical biology”, 2006
  • Keynote Speaker, FASEB Summer Conference on Lysophospholipids, 2005
  • Foreign Member of the Hungarian Academy of Sciences, 2004
  • Takeda Foundation Lecturer, 2001
  • Established Investigator of the American Heart Association, 1997-2000.

Editorial Boards

  • Journal of Biological Chemistry
  • Biochimica and Biophysica Acta
  • Guest Editor, J. Cellular Biochemistry
  • Guest Editor, BBA Special Issue on Lysophospholipids 2004 and 2008
  • Chair, 2003, Co-Chair, 2001, FASEB Summer Conference on Lysolipids and Related Bioactive Mediators in Biology and Diseases 2000
  • IUPHAR Nomenclature Committee on Lysolipid Receptors

Research Support

NIH R01 HL 079004 Tigyi (PI)
Analysis of LPA Signaling through the GPCR-PPARg axis
Major goals of project: To understand the role of LPA GPCR and PPARgamma receptors in neointima formation.
Role: PI

NIH R01 HL 061469 Tigyi (PI)
Therapeutically promising phospholipid growth factors
The goal of this project was to isolate and characterize a novel group of naturally occurring lipids, now known as the phospholipids growth factor (PLGF) family, and to investigate the structure-activity
relationship of the PLGF receptors (PLGFR).
Role: PI

NIH R01 CA 092160 Tigyi (PI)
Ligand recognition by phospholipid growth factor receptors
The goals of this project was to develop and validate a refined computational model for the interaction of SPP with the EDG1 receptor, identify residues conferring specificity for sphingolipids in the EDG3/5/6/8 receptor subfamily, and to identify residues involved in glycerolipid recognition in the EDG2/4/7 receptor subfamily
Role: PI

USAMRMC Proposal Number 06171001 Tigyi (PI)
Novel Methods for Imaging PET Biomarkers and Gene Therapy of Cancer
The objective of this proposal is to set up two core laboratories at the university of Tennessee Health Science Center for Viral Vector Core and Microfluidic Chemistry services.
Role: PI

NIH R01 HL 084007 Parrill (PI)
Computational Approach to Ligand Discovery for LPA GPCR and PPAR.
The goal of this project is to elucidate the structure of the extracellular loops of lysophospholipid receptors .
Role: Co-PI

NIH RO3 AI 0170942 Naren (PI)
V. cholerae as a bioterror agent: New means of treating a potential pandemic
Goals: The aims of this grant proposal are to test if foods rich in LPA will inhibit CTX-induced diarrhea in mice. And to test if metabolically stabilized synthetic LPA-receptor agonists exhibit potent anti-diarrheal properties (compared to LPA).
Role: Collaborator

AI 078514 Tigyi (PI)
NIH/NIAID
Development of a Novel Gastrointestinal Radiomitigator
The main objective of this grant is to determine the therapeutic efficacy of octadecenyl thiophosphate, a novel radiomitigator using mouse and non-human primates of radiation-induced mucositis.
Role: PI

Selected Publications

Publications: 2003-Present

1. Fujiwara, Y., Sebok, A., Meakin, S., Kobayashi, T.,Murakami-Murofushi, K., Tigyi, G. (2003) The endogenous lipid mediator cyclic-phosphatidic acid mimics the actions of neurotrophins in embryonic hippocampal neurons. J. Neurochem. 87:1272-83.
2. Yue, J., Yokoyama, K., Balazs, L., Baker, D.L., Pilquil, C., Brindley, D.N., Tigyi, G. (2003) Mice with Transgenic Over-expression of Lipid Phosphate Phosphatase-1 Display Reproductive and Hair Growth Deficits without Alteration in Circulating Lysophosphatidate Level. Cellular Signaling 16: 385-399.
3. Meyer zu Heringdorf, D.,Liliom, K., Schäfer, M., Danneberg, Jaggar, J., Tigyi, G., and Karl H. Jakobs. (2003) Photolysis of intracellular caged sphingosine-1-phosphate causes Ca2+ mobilization independently of G protein-coupled receptors. FEBS Lett. 543:443-449.
4. Haserück, N., Erl, Tigyi, G., Ohlmann, P., Ravanat, K., Gachet, C., Siess, W. (2004) The plaque lipid lysophosphatidic acid stimulates platelet aggregation and platelet-monocyte aggregate formation in whole blood Involvement of P2Y1 and P2Y12 receptors. Blood 103:2585-92.
5. Siess, W. and Tigyi, G. (2004) Thrombogenic and atherogenic activities of lysophosphatidic acid. J. Cell. Biochem. 92:1086-94.
6. Zhang, C., Baker, D.L., Yasuda, S., Makarova, N., Balazs, L., Johnson, L.R., Marathe, G.K., McIntyre, T.M., Xu, Y., Prestwich, G.D., Byun, H.-S., Bittman R., and Tigyi, G. (2004) Lysophosphatidic Acid Induces Neointima Formation Through PPAR? Activation J.Exp. Med. 199:763-774.
7. Deng, W., Poppleton, H., Yasuda, S., Makarova, N., Shinozuka, Y., Wang, D-A., Johnson, L.R., Patel T.B., and Tigyi, G. Optimal LPA-induced DNA Synthesis and Cell Migration but Not Survival Require Intact Autophosphorylation Sites of the EGF Receptor. (2004) 279: 47871-47880.
8. Li, C. Dandridge, K.S., Harris, E.L., Roy, K., Jackson, J.S., Makarova, N.V., Farrar, P.L., Tigyi, G. and Naren, A.P. Lysophophatidic inhibition of secretory diarrhea through CFTR-dependent protein interactions. (2004) Science ?in review.
9. Goetzl EJ, Tigyi G. Lysophospholipids and their G protein-coupled receptors in biology and diseases. (2004) J Cell Biochem. 92(5):867-8.
10. Krump-Konvalinkova, V., Yasuda, S., Rubic, T, Makarova, N. Mages, J., Erl,W., Vosseler, C., Kirkpatrick, C.J., Tigyi, G., Siess, W. (2005) Stable knock-down of the sphingosine-1-phosphate receptor S1P1 influences multiple functions of human endothelial cells. Atheroscler.Vasc. Biol25(3):546-52
11. Inagaki, Y., Kohno, T., Pham, T-C, T, Fujiwara, Y., Igarashi, Y., Tigyi, G., and Parrill, A.L. (2005) Distinct and Conserved Residues Mediate Sphingosine-1-Phosphate Recognition in S1P4 within the Endothelial Differentiation Gene Family of Receptors. Biochem. J. 89:187-95.
12. Jo, E, Sanna, M.G., Gonzalez-Caberra, P.J., Thangada, S., Tigyi, G., Osborne, D.A., Hla, T., Parrill, A.L., Rosen, H. (2005) S1P1-selective in vivo-active agonists from high throughput screening: Off the shelf chemical probes of receptor interactions, signaling and fate. Chem. Biol. 12:703-15.
13. Li, C. Dandridge, K.S., Harris, E.L., Roy, K., Jackson, J.S., Fujiwara, Y., Makarova, N.V., Farrar, P.L., Tigyi, G. and Naren, A.P. Lysophophatidic inhibition of secretory diarrhea through CFTR-dependent protein interactions. (2005) J.Exp. Med. 202:975-86 .
14. Nusser, N., Gosmanova, E., Fujiwara, Y., Makarova, N., Guo, F., Luo, Y., Zheng,Y., and Tigyi, G. (2006) Phosphorylation-regulated Target Selection of RhoA Is Required for NGF-Induced Neurite Outgrowth Cellular Signaling 18: 704-714.
15. Durgam,G.G.,Virag, T., Walker,M.D.,Tsukahara,R., Yasuda, S., Liliom,K., van Meeteren, L.A., Moolenaar,W.H., Wilke, N., Siess,W., Tigyi, G., and Miller, D.D. (2005) Synthesis, Structure-Activity Relationships, and Biological Evaluation of Fatty Alcohol Phosphates as Lysophosphatidic Acid Receptor Ligands, Activators of PPAR? and Inhibitors of Autotaxin. J.Med.Chem. 48(15):4919-30.
16. Waters, C.M., Connell, M., Gorchkova, I., Long, J., Fujiwara, Y., Belmonte, K., Tigyi, G., Natarajan,W., Pyne, S., and Pyne, N.J. (2006) The sphingosine 1-phosphate receptor-1 inverse agonist SB649146 reduces platelet-derived growth factor-induced cell migration. FASEB J 20(3):509-11.
17. Fujiwara, Y, Sardar, V., Tokumura, A., Baker, D.L., Murakami-Murofushi, K., Parrill, A., and Tigyi, G. (2005) Identification of residues responsible for ligand recognition and regioisomeric selectivity of LPA receptors expressed in mammalian cells ? J. Biol. Chem. 280:35038-50.
18. Xu, Y, Tsukahara, R., Fujiwara, R, Tigyi, G., Prestwich, G. (2006) Phosphonothioate and Fluoromethylene Phosphonate Analogues of Cyclic Phosphatidic Acid: Novel pKa Matched LPA Receptor Antagonists. J.Med. Chem. 49:5309-15
19. Gududuru, V., Tsukahara, R., Makarova, N., Fujiwara, Y., Pigg, K.R., Baker, D.L., Tigyi, G., Miller, D.D. (2006) Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors. Biomed. Chem.Lett. 5;16(2):451-6.
20. Drugam, G., Tsukahara, R., Makarova, N., Fujiwara, Y., Pigg, K.R., Baker, D.L., Parrill, A., Tigyi, G., Miller, D.D. (2006) Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands. Biomed. Chem. Lett. 6(3):633-40.
21. Li, Z, Baker, D.L., Tigyi, G., Bittman R. (2006) Synthesis of Photoactivatable Analogues of Lysophosphatidic Acid and Covalent Labeling of Plasma Proteins. J. Org.Chem. 20;71:629-35
22. Qian, L., Xu, Y., Simper, T., Aoki, J., Tsukahara, R., Makarova, N., Yu, S., Mills, G.B., Tigyi, G., Prestwich, G.D. (2006) Phosphorothioate and fluoromethylene phosphonate analogues of cyclic phosphatidic Acid: novel antagonists of lysophosphatidic Acid receptors. Chem. Med. Chem. 1:376-383.
23. Zhang, H., Tsukahra, R., Tigyi, G., and Prestwich, G. (2006) Synthesis of Cyclic Phosphonate Analogues of (Lyso)phosphatidic Acid Using a Ring-Closing Metathesis Reaction. J. Org. Chem. 71(16):6061-6.
24. Tsukahara, T., Tsukahara, R., Yasuda, S., Makarova, N., Valentine,W.J., Allison, P., Yuan, H., Baker,D.L., Li, Z., Bittman, R., Parrill, A., Tigyi, G. (2006) Different Residues Mediate Recognition of 1-O-Oleyl-Lysophosphatidic Acid and Rosiglitazone in the Ligand Binding Domain of PPAR?1. J. Biol. Chem. 281(6):3398-407.
25. Long,J.S., Darroch, P,. Tate, R.J., Tolan, D.J., Tigyi, G., Pyne, N.J., Pyne, S. (2006) Lipid phosphate phosphatases are functionally active as dimers. Biochem. J. 394:495-500.
26. Baker, D.L., Fujiwara, Y., Pigg, K.R., Tsukahara, R., Kobayashi, S., Uchiyama, A., Murakami-Murofushi, K., Murofushi, H., Koh, E., Bandle, R., Byun, H.-S., Bittman, R., Murph, M., Fan, D., Mills, G.B., Tigyi, G. (2006) Carba Analogs of Cyclic Phosphatidic Acid Are Selective Inhibitors of Autotaxin and Cancer Invasion. J. Biol. Chem. 281:22786-93.
27. Waters C.M, Saatian B., Moughal N.A., Zhao Y., Tigyi G, Natarajan V., Pyne S., Pyne N.J. Integrin signalling regulates the nuclear localization and function of the lysophosphatidic acid receptor-1 (LPA 1) in mammalian cells. (2006) Biochem J. 398:55-62.
28. Moughal, N.A., Waters, C.M., Valentine, W.J., Connell, M., Crook, B., Harrison, S., Richardson, J., Tigyi, G., Pyne, S., Pyne, N.J. (2006) Cross talk regulation between TrkA and lysophosphatidic acid receptor signaling systems in mammalian cell. J. Neurochem ?10: 1471-81.
29. Yue, J. and Tigyi, G. (2006) MicroRNA trafficking and Human cancer. Cancer Biol Ther. 5:573-78.
30. Liliom, K., Tsukahara, T., Tsukahara, R., Zelman-Femiak, M., Swiezewska, E., and Tigyi, G. (2006) Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: inhibition of LPA GPCR and activation of PPARg???Biochim.Biophys. 1761(12):1506-14.
31. Uchiyama, A., Mukai, M., Kobayashi, S., Kawai, N., Enoki, S., Tanaka, S., Murofushi, H., Niki, T., Kobayashi, T., Tigyi, G., Murakami-Murofushi, K., (2007) Inhibition of tumor cell invasion and metastasis by novel carba-derivatives of cyclic phosphatidic acid. Biochim.Biophys. Acta 1771(1):103-12.
32. Naor, M, Walker, D.M., Tigyi, G., Vanbrocklyn, J., Parrill, A. (2006) Sphingosine 1-Phosphate pKa and Binding Constants: Intramolecular and Intermolecular Influences. J. Mol.Graph.Mod. ?Sep;26(2):519-28.
33. Pilquil, C., Dewald, J., Cherney, A., Gorshkova, I., Tigyi, G., English, D., Natarajan, W., and Brindley, D.N. (2006) Lipid Phosphate Phosphatase-1 Regulates Lysophosphatidate-induced Fibroblasts Migration by Controlling Phospholipase D2-dependent Phosphatidate Generation. J. Biol. Chem. 281(50):38418-29
34. Gajewiak, J., Yu, S., Tsukahara, R., Tigyi, G., Mills, G.B., Prestwich, G.D. (2007) Alkoxymethylenephosphonate Analogues of (Lyso)phosphatidic acid: Synthesis and Biological Activity. J. Org. Chem. 2(5):679-690.
35. Jiang, G., Xu, Y., Fujiwara, Y., Tsukahara, R., Tsukahara, R., Tigyi, G., and Prestwich, G. D. (2007) ?-Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA. ChemMedChem. 2007 2:679-690.
36. Deng, W., E, S., Tsukahara, R., Valentine, W., Durgam, G., Gududuru,V., Balazs, L., VanMiddlesworth, L., Johnson, L.R., Manickam, V., Arsura, M., Parrill, A.L., Miller, D.D. and Tigyi, G. (2007) The LPA2 Receptor is Required for Protection Against Radiation-Induced Intestinal Injury. Gastroenterology 132(5):1834-51.
37. Fujiwara, Y., Osborne, D.A., Walker, M.D., Wang, D-A., Bautista,D.D., Liliom, K., Van Brocklyn, J.R., Parrill, A.L., Tigyi, G. (2007) Identification of the hydrophobic ligand binding pocket of the s1p1 receptor. J Biol. Chem. 282(4):2374-85.
38. Hao F, Tan M, Xu X, Han J, Miller DD, Tigyi G, Cui MZ. (2007) Lysophosphatidic acid induces prostate cancer PC3 cell migration via activation of LPA(1), p42 and p38alpha. Biochim Biophys Acta. 1771(7):883-92.
39. Pyne NJ, Waters CM, Long JS, Moughal NA, Tigyi G, Pyne S. (2007) Receptor tyrosine kinase-G-protein coupled receptor complex signaling in mammalian cells. Adv Enzyme Regul. Adv Enzyme Regul. 47:271-80.
40. Valentine,W.V, Fujiwara, Y., Tsukahara R., and Tigyi, G. (2007) Lysophospholipid Signaling: Beyond the EDGs. Biochem. Biophys. Acta Aug 25; [Epub ahead of print]
41. Lin, F-T. , Lai, J-Y., Makarova, N., Tigyi, G., and Lin W.C. (2007) The LPA2 Receptor Mediates Down-Regulation Of Siva-1 To Promotes Cell Survival J. Biol. Chem. [Epub ahead of print, 10-26-07].